Pyrrolopyrimidines as CFTR Potentiators

ABSTRACT

The present invention relates to methods of using compounds of Formula I,wherein R1a, R1b, R2, R3, R4, W, Y, and Z are as described herein, and pharmaceutically acceptable salts thereof. The compounds are potentiators of Cystic Fibrosis Transmembrane conductance Regulator (CFTR). The invention also discloses pharmaceutical compositions comprising the compound, optionally in combination with additional therapeutic agents, and methods of potentiating, in mammals, including humans, CFTR by administration of the compounds. These compounds are useful for the treatment of cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, Diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis, Sjögren&#39;s Syndrome, and other CFTR associated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/578,277 filed Sep. 20, 2019, which is a continuation of U.S.application Ser. No. 16/377,005 filed Apr. 5, 2019, now U.S. Pat. No.10,494,374 issued Dec. 3, 2019, which is a divisional of U.S.application Ser. No. 15/815,809 filed Nov. 17, 2017, now U.S. Pat. No.10,301,315 issued May 28, 2019, which claims priority to U.S.Provisional Application 62/423,919 filed Nov. 18, 2016, the contents ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to small molecule potentiators of CysticFibrosis Transmembrane conductance Regulator (CFTR). This invention alsorelates to pharmaceutical compositions comprising the potentiators,optionally in combination with additional therapeutic agents, andmethods of potentiating, in mammals, including humans, CFTR byadministration of the small molecule CFTR potentiators. The presentinvention also relates to the treatment of cystic fibrosis and otherdisorders in mammals, including humans, with the CFTR potentiators. Moreparticularly, this invention relates to2,5,6,7-tetrasubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivativesuseful for the treatment of cystic fibrosis (CF), asthma,bronchiectasis, chronic obstructive pulmonary disease (COPD),constipation, Diabetes mellitus, dry eye disease, pancreatitis,rhinosinusitis, Sjögren's Syndrome, and other CFTR associated disorders.

BACKGROUND OF THE INVENTION

Cystic fibrosis (CF) is the most common lethal genetic disease affectingCaucasians. CF is an autosomal recessive disease with an incidence ofbetween 1 in 2000 and 1 in 3000 live births (Cutting, G. R., Accurso,F., Ramsey, B. W., and Welsh, M. J., Online Metabolic & Molecular Basesof Inherited Disease, McGraw-Hill, 2013). There are over 70,000 peopleaffected worldwide, of which approximately 33,000 are in the UnitedStates (www.cff.org/What-is-CF/About-Cystic-Fibrosis/). The hallmarks ofCF are excessive mucus secretion and defective mucus clearance resultingin obstruction, infection and inflammation in the airways; pancreaticinsufficiency; and elevated sweat chloride concentration. CF is amultisystem disease affecting the lungs, pancreas, and gastrointestinal,hepatobiliary, and reproductive tracts (R. D. Coakley et al., in CysticFibrosis, Eds. Hodson, M., Geddes, D., and Bush, A., Edward Arnold,Third Ed., 2007, pp. 59-68).

For most patients, there is a high burden of care for supportivetherapies that do not address the root cause of the disease. Supportivetherapies include physical airway clearance techniques, inhaledmedications (mucolytics, antibiotics, and hypertonic saline), oralanti-inflammatory drugs, pancreatic enzyme replacements, and nutritionalsupplements (Cystic Fibrosis Foundation Patient Registry 2011 AnnualData Report to the Center Directors, Cystic Fibrosis Foundation,Bethesda, Md., 2012). The median age of survival for patients withcystic fibrosis is into the fourth decade of life.

Cystic fibrosis is caused by mutations in the gene for CFTR (CysticFibrosis Transmembrane conductance Regulator), an ion channel found inepithelia as well as other tissues. CFTR is found at the apical membraneof epithelial cells in the airways, intestine, pancreas, and sweatglands (G. R. Cutting, Accurso, F., Ramsey, B. W., and Welsh, M. J.,Online Metabolic & Molecular Bases of Inherited Disease, McGraw-Hill,2013). Mutations in CFTR have been classified into six types (Welsh, M.J., and Smith, A. E., Cell, 1993, 73, 1251-1254 and Sloane, P. A., andRowe, S. M., Curr. Opin. Pulm. Med., 2010, 16, 591-597): 1) prematuretermination due to deletion, nonsense, or frameshift mutations, 2)defective trafficking out of the endoplasmic reticulum due to improperfolding, 3) improper gating, 4) reduced conductance due to changes inthe channel pore, 5) reduced production of channel due to alteredsplicing, and 6) increased endocytosis from the plasma membrane.

Nearly 2,000 different mutations in CFTR are known to cause CF. Deletionof Phe508 of CFTR (F508del) occurs in approximately 70% of CFTR alleles(Bobadilla, J. L. et al., Human Mutation, 2002, 19, 575-606).Approximately 50% of patients are F508del homozygotes and ca. 40% areheterozygotes so that at least one copy of F508del is present in about90% of patients. G551D is the third most common mutation and is presentin about 4% of patients (Cystic Fibrosis Foundation Patient Registry2011 Annual Data Report to the Center Directors, Cystic FibrosisFoundation, Bethesda, Md., 2012).

The F508del mutation causes loss of CFTR function due to both reducedchannel density and impaired channel gating. Channel density at theapical membrane is reduced due to protein misfolding. Misfolded CFTR isrecognized by cellular quality control mechanisms and degraded (Ward, C.L. and Kopito, R. R., J. Biol. Chem., 1994, 269, 25710-25718). F508delfunction is further reduced because it has a significantly reducedchannel open probability (gating defect) (Dalemans, W. et al., Nature,1991, 354, 526-528). The G551D mutation results in a protein with normalfolding but impaired gating (lllek, B. et al., Am. J. Physiol., 1999,277, C833-C839).

Small molecules called ‘correctors’ have been shown to reverse thefoIding/traffieking defect of F508del CFTR and increase the density ofCFTR channels at the plasma membrane (Pedemonte, N. et al., J. Clin.Invest., 2005, 115, 2564-2571, Van Goor, F. et al., Am. J. Physiol. LungCell. Mol. Physiol., 2006, 290, L1117-1130, Van Goor, F. et ai., Proc.Nat. Acad. Sci. USA, 2011, 108, 18843-18848). ‘Potentiators’ are smallmolecules that increase the channel open probability of mutant CFTR,reversing the gating defect. Pharmacological repair of F508del isthought to require at least a corrector and a potentiator to address thefolding and gating defects while G551D may see benefit from apotentiator only.

Kalydeco® (ivacaftor, VX-770) is a marketed potentiator that improvesthe gating characteristics of G551D. In G551D patients, it substantiallyimproved lung function (percent predicted FEV₁ increased 10-13%),allowed weight gain, and reduced the frequency of pulmonaryexacerbations (Ramsey, B. W. et al., New Eng. J. Med., 2011, 365,1663-1672, Davies, J. C. et al., Am. J. Resp. Crit. Care Med., 2013,187, 1219-1225). Kalydeco® is also approved for people with G1244E,G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R mutations andapplication to other mutations including those with partial function isbeing investigated.

While monotherapy with Kalydeco® did not lead to any appreciableimprovement in F508del homozygote patients (Flume, P. A. et al., Chest,2012, 142, 718-724), a combination of a corrector (VX-809, lumacaftororVX-661, tezacaftor) with Kalydeco® resulted in a modest improvement inlung function (percent predicted FEV₁ increased 3-4%) (Wainwright, C. E.et al., N. Engl. J. Med., 2015, 373, 220-231, Pilewski, J. M. et al., J.Cystic Fibrosis, 2015, 14, Suppl. 1, S1). The VX-809 plus Kalydeco®combination (called Orkambi®) is a marketed therapy for F508delhomozygote patients.

For both the G551D and the F508del patient populations, improvedtherapies are expected to provide further benefit to patients. MostG551D patients are G551D/F508del compound heterozygotes and treatmentwith the combination of the corrector VX-661 plus Kalydeco® resulted ina further increase in lung function over Kalydeco® alone (Pilewski, J.M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1).

Mutations in CFTR that are associated with moderate CFTR dysfunction arealso evident in patients with conditions that share certain diseasemanifestations with cystic fibrosis but do not meet the diagnosticcriteria for cystic fibrosis. In these patients, CFTR dysfunction atepithelial cell layers can occur and give rise to abnormal mucus andendocrine secretions that are similar to those that characterize cysticfibrosis. CFTR dysfunction may also be acquired. Chronic inhalation ofparticulate irritants, including cigarette smoke, pollution, and dustcan result in reduced CFTR ion-channel activity.

Modulation of CFTR activity may also be beneficial for other diseasesnot directly caused by mutations in CFTR, such as secretory diseases andother protein folding diseases mediated by CFTR. CFTR regulates chlorideand bicarbonate flux across the epithelia of many cells to control fluidmovement, protein solubilization, mucus viscosity, and enzyme activity.Defects in CFTR can cause blockage of the airway or ducts in manyorgans, including the liver and pancreas. Potentiators are compoundsthat enhance the gating activity of CFTR present in the cell membrane.Any disease which involves thickening of the mucus, impaired fluidregulation, impaired mucus clearance, or blocked ducts leading toinflammation and tissue destruction could be a candidate forpotentiators. Therefore, there exists a significant therapeutic need fornovel small molecules that act as potentiators of CFTR.

In addition to cystic fibrosis, CFTR-related diseases or other diseaseswhich may benefit from modulation of CFTR activity include, but are notlimited to, asthma, bronchiectasis, chronic obstructive pulmonarydisease (COPD), constipation, diabetes mellitus, dry eye disease,pancreatitis, rhinosinusitis, and Sjögren's Syndrome.

SUMMARY OF THE INVENTION

A first embodiment of a first aspect of the present invention is acompound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

W is selected from the group consisting of phenyl, which is optionallyfused with a five to six membered cycloalkyl or a five to six memberedheterocycloalkyl comprising one, two, three, or four heteroatomsselected independently for each occurrence from the group consisting ofN, O and S(O)_(n);

a five to ten membered heteroaryl comprising one, two, three, or fourheteroatoms selected independently for each occurrence from the groupconsisting of N, O and S(O)_(n);

a four to seven membered heterocycloalkyl comprising one, two, three, orfour heteroatoms selected independently for each occurrence from thegroup consisting of N, O, and S(O)_(n); and

C₃-C₇cycloalkyl;

wherein the phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl areoptionally substituted with one, two, three, four, or five R⁵;

Y is a five membered heteroaryl comprising one, two, three, or fourheteroatoms selected independently for each occurrence from the groupconsisting of N, O and S(O)_(n); wherein the heteroaryl is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of halo, C₁-C₆alkyl, and C₁-C₆haloalkyl;

Z is selected from the group consisting of phenyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, a five or six membered heteroaryl comprising one, twoor three heteroatoms selected independently for each occurrence from thegroup consisting of N, O and S(O)_(n), and a four to seven memberedheterocycloalkyl comprising one, two, or three heteroatoms selectedindependently for each occurrence from the group consisting of N, O andS(O)_(n); wherein said phenyl, alkyl, cycloalkyl, heteroaryl, andheterocycloalkyl are each independently optionally substituted with one,two, three, four, or five R⁶;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of —H, —OH, halo, C₁-C₆alkyl, C3-C₇cycloalkyl, and a four toseven membered heterocycloalkyl comprising one, two, or threeheteroatoms each independently selected from the group consisting of N,O and S(O)_(n); wherein the C₁-C₆alkyl group is optionally substitutedwith one, two, or three substituents each independently selected fromthe group consisting of halo, —OH, C₁-C₃alkyoxy, C₃-C₇cycloalkyl, and afour to seven membered heterocycloalkyl comprising one, two, or threeheteroatoms each independently selected from the group consisting of N,O and S(O)_(n); and wherein each C₃-C₇cycloalkyl and each four to sevenmembered heterocycloalkyl are optionally substituted with one, two orthree substituents independently selected for each occurrence from thegroup consisting of —OH, halo, and C₁-C₆alkyl;

or R^(1a) and R^(1b) taken together with the carbon to which they areattached form a C₃-C₇cycloalkyl or a four to seven memberedheterocycloalkyl comprising one, two, or three heteroatoms eachindependently selected from the group consisting of N, O and S(O)_(n);and wherein each C₃-C₇cycloalkyl and each four to seven memberedheterocycloalkyl are optionally substituted with one, two or threesubstituents each independently selected from the group consisting of—OH, halo, and C₁-C₆alkyl.

R² is selected from the group consisting of —H, halo, —CN, C₁-C₆alkyland C₁-C₆haloalkyl;

R³ and R⁴ are independently selected for each occurrence from the groupconsisting of —H, C₁-C₆alkyl and C₁-C₆haloalkyl;

R⁵ at each occurrence is independently selected from the groupconsisting of halo, —CN, C₁-C₆alkyl, C₁-C₆haloalkyl, —OR⁷, —N(R⁷)₂,—N(R⁷)C(═O)R⁷, —SR⁷, oxo, C₂-C₇alkoxyalkyl, —S(═O)₂C₁-C₆alkyl, —C(═O)R⁷,and a five membered heteroaryl comprising one, two, three, or fourheteroatoms selected independently for each occurrence from the groupconsisting of N, O and S(O)_(n), wherein the heteroaryl is optionallysubstituted with one, two, or three substituents independently selectedfor each occurrence from the group consisting of halo, —CN, C₁-C₆alkyl,C₁-C₆haloalkyl, —OR⁷, —N(R⁷)₂ and —SR⁷;

R⁶ at each occurrence is independently selected from the groupconsisting of halo, C₁-C₆alkyl and C₁-C₆haloalkyl, —OR⁷, —N(R⁷)₂, and—SR⁷;

R⁷ is independently selected for each occurrence from the groupconsisting of —H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, andC₁-C₆alkylC₃-C₇cycloalkyl; and

n at each occurrence is independently 0, 1, or 2.

A second embodiment of the first aspect of the present invention is thecompound of the first embodiment, wherein R³ and R⁴ are both —H; or apharmaceutically acceptable salt thereof.

A third embodiment of the first aspect of the present invention is thecompound of the second embodiment, wherein Y is pyrazole, triazole,imidazole, or isoxazole, each optionally substituted with C₁-C₆alkyl; ora pharmaceutically acceptable salt thereof.

A fourth embodiment of the first aspect of the present invention is thecompound of the second embodiment or a pharmaceutically acceptable saltthereof, wherein the moiety Y—Z is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

A fifth embodiment of the first aspect of the present invention is thecompound of the third embodiment, wherein W is phenyl, optionallysubstituted with one, two, or three R⁵; or a pharmaceutically acceptablesalt thereof.

A sixth embodiment of the first aspect of the present invention is thecompound of the third embodiment, wherein W is selected from the groupconsisting of pyrimidinyl, pyridinyl, pyrazinyl, and pyrazolyl eachoptionally substituted with one, two, or three R⁵; or a pharmaceuticallyacceptable salt thereof.

A seventh embodiment of the first aspect of the present invention is thecompound of the third embodiment, wherein W is C₃-C₇cycloalkyl,optionally substituted with one, two, or three R⁵; or a pharmaceuticallyacceptable salt thereof.

An eighth embodiment of the first aspect of the present invention is thecompound of the six embodiment wherein W is

optionally substituted with one, two, or three R⁵;R⁵ at each occurrence is independently selected from the groupconsisting of —OCH₃, —CHF₂, —CF₃, and —N(CH₃)₂; or a pharmaceuticallyacceptable salt thereof.

A ninth embodiment of the first aspect of the present invention is thecompound of the third embodiment wherein Z is selected from the groupconsisting of phenyl, C₃-C₇cycloalkyl, and C₁-C₆alkyl, each optionallysubstituted with one, two, or three R⁶; or a pharmaceutically acceptablesalt thereof.

A tenth embodiment of the first aspect of the present invention is thecompound of the ninth embodiment wherein Z is phenyl, optionallysubstituted with one or two fluoro or chloro; or a pharmaceuticallyacceptable salt thereof.

An eleventh embodiment of the first aspect of the present invention isthe compound of the ninth embodiment or a pharmaceutically acceptablesalt thereof, wherein Z is C₁-C₆alkyl or C₃-C₇cycloalkyl; or apharmaceutically acceptable salt thereof.

A twelfth embodiment of the first aspect of the present invention is thecompound of the second embodiment, wherein R² is selected from the groupconsisting of: —H, —CN, and —Br; or a pharmaceutically acceptable saltthereof.

A thirteenth embodiment of the first aspect of the present invention isa compound selected from the group consisting of

-   4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   6-bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[4-(cyclopropyloxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-cyclobutyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(6-methoxypyridin-3-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(5-fluoro-2-methoxypyridin-3-yl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[6-(difluoromethoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[2-(2,4-difluorophenyl)-1H-imidazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-5-[2-(difluoromethoxy)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   5-(2-fluoro-4-methoxyphenyl)-7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(3-fluoro-4-methylphenyl)-7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[4-(2H-1,2,3-triazol-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-ethoxy-3-fluorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chloro-2-methoxyphenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[4-(difluoromethoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-(methylsulfanyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[4-(difluoromethoxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[2-fluoro-4-(methylsulfanyl)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chloro-3-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(3-chloro-5-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   4-(4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile;-   5-[4-(cyclopropyloxy)phenyl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-methoxypyrimidin-5-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[2-(dimethylamino)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1R)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(S)-cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(5-fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-[2-(difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   5-(4-chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-({1-[4-(difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   4-amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;    and-   4-amino-7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   or a pharmaceutically acceptable salt thereof.-   A fourteenth embodiment of the first aspect of the present invention    is a compound selected from the group consisting of-   7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;    and-   4-amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;-   or a pharmaceutically acceptable salt thereof.

A fifteenth embodiment of the first aspect of the present invention isthe compound7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine or a pharmaceuticallyacceptable salt thereof.

A sixteenth embodiment of the first aspect of the present invention isthe compound4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.

A seventeenth embodiment of the first aspect of the present invention isthe compound4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.

An eighteenth embodiment of the first aspect of the present invention isthe compound4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.

A nineteenth embodiment of the first aspect of the present invention isthe compound4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.

A first embodiment of a second aspect of the present invention is amethod of treating cystic fibrosis, asthma, bronchiectasis, chronicobstructive pulmonary disease (COPD), constipation, Diabetes mellitus,dry eye disease, pancreatitis, rhinosinusitis, or Sjögren's Syndrome ina patient in need of treatment thereof, the method comprisingadministering a therapeutically effective amount of a compound, orpharmaceutically acceptable salt of said compound, according to any oneof the first through nineteenth embodiments of the first aspect, to apatient in need of treatment thereof.

A second embodiment of the second aspect of the present invention is amethod for treating cystic fibrosis in a patient in need of treatmentthereof, the method comprising administering a therapeutically effectiveamount of a compound, or pharmaceutically acceptable salt of saidcompound, according to any one of the first through nineteenthembodiments of the first aspect, to a patient in need of treatmentthereof.

A first embodiment of a third aspect of the present invention is thecompound or pharmaceutically acceptable salt thereof according to anyone of the first through nineteenth embodiments of the first aspect foruse in the treatment of cystic fibrosis.

A first embodiment of a fourth aspect of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound according to any one of the first through nineteenthembodiments of the first aspect, or a pharmaceutically acceptable saltthereof together with a pharmaceutically acceptable carrier.

A second embodiment of the fourth aspect of the present invention is thepharmaceutical composition of the first embodiment of the fourth aspect,further comprising one or more additional therapeutic agents.

A third embodiment of the fourth aspect of the present invention is thepharmaceutical composition of the second embodiment of the fourthaspect, wherein the one or more additional therapeutic agents areselected from the group consisting of a CFTR potentiator, a CFTRcorrector, an epithelial sodium channel (ENaC) inhibitor, a CFTRamplifier, a CFTR stabilizer, a read-through agent, an oligonucleotidepatch, an autophagy inducer, and a proteostasis modulator.

A fourth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the CFTR potentiator at each occurrence is selected from thegroup consisting of VX-770 (Ivacaftor), GLPG-1837, GLPG-2451, QBW-251,FDL-176, FDL-129, CTP-656, and PTI-P271.

A fifth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the CFTR corrector at each occurrence is selected from the groupconsisting of VX-809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152,VX-440, VX-659, GLPG2737, P247-A, GLPG-2222, GLPG-2665, GLPG-2851,FDL-169, and PTI-C1811.

A sixth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the epithelial sodium channel (ENaC) inhibitor at eachoccurrence is selected from the group consisting of SPX-101, QBW-276 andVX-371.

A seventh embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the CFTR amplifier at each occurrence is selected from the groupconsisting of PTI-428 and PTI-130.

An eighth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the CFTR stabilizer is N-91115 (Cavosonstat).

A ninth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the read-through agent is ataluren (PTC124).

A tenth embodiment of the fourth aspect of the present invention is apharmaceutical composition of the third embodiment of the fourth aspect,wherein the autophagy inducer at each occurrence is selected from thegroup consisting of CX-4945 and the combination of cysteamine andepigallocatechin gallate (EGCG).

A first embodiment of a fifth aspect of the present invention is amethod for treating cystic fibrosis in a patient in need of treatmentthereof, the method comprising administering the pharmaceuticalcomposition according to any one of the first through tenth embodimentsof the fourth aspect to the patient in need of treatment thereof.

A first embodiment of a sixth aspect of the present invention is thepharmaceutical composition according to any one of the first throughtenth embodiments of the fourth aspect for use in the treatment ofcystic fibrosis.

Definitions

The term “alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen); in one embodiment from one to six carbonatoms (i.e., C₁-C₆alkyl). Examples of such substituents include methyl,ethyl, propyl (including n-propyl and isopropyl), butyl (includingn-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl andthe like.

The term “haloalkyl” refers to an alkyl in which at least one hydrogenon the alkyl is replaced with a halogen atom. The term “C₁-C₆ haloalkyl”refers to a C₁-C₆ alkyl group, as defined herein, in which one, two,three, four, five, or six hydrogen atoms are replaced by halogen. Incertain embodiments in which two or more hydrogen atoms are replacedwith halogen atoms, the halogen atoms are all the same as one another.In other embodiments in which two or more hydrogen atoms are replacedwith halogen atoms, the halogen atoms are not all the same as oneanother. Examples of haloakyls include: chloromethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1, 1-difluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2-chloro-3-fluoropentyl, and the like.

The term “alkoxy” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen) which is in turn attached to an oxygen atom;in one embodiment from one to six carbon atoms (i.e., C₁-C₆alkoxy).Examples of such substituents include methoxy, ethoxy, propoxy(including n-propoxy and isopropoxy), butoxy (including n-butoxy,isobutoxy, sec-butoxy and tert-butoxy), pentoxy and the like.

The term “cycloalkyl” refers to a carbocyclic substituent obtained byremoving a hydrogen atom from a saturated carbocyclic molecule andhaving the specified number of carbon atoms. In one embodiment, acycloalkyl substituent has three to seven carbon atoms (i.e.,C3-C₇cycloalkyl). Examples of cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term“cycloalkyl” includes mono-, bi- and tricyclic saturated carbocycles, aswell as bridged and fused ring carbocycles, as well as spiro-fused ringsystems.

As used herein, the term “heterocycloalkyl” refers to a monocyclic ringsystem containing the heteroatoms N, O or S(O)_(n) as specified. Theterm “heterocycloalkyl” refers to a substituent obtained by removing ahydrogen from a saturated or partially saturated ring structurecontaining the specified number of ring atoms, wherein at least one ofthe ring atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. If theheterocycloalkyl substituent is in turn substituted with a group orsubstituent, the group or substituent may be bound to a nitrogenheteroatom, or it may be bound to a ring carbon atom, as appropriate. Insome instances, the number of atoms in a cyclic substituent containingone or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) isindicated by the prefix “x to y membered”, wherein x is the minimum andy is the maximum number of atoms forming the cyclic moiety of thesubstituent. Thus, for example, “four to seven memberedheterocycloalkyl” refers to a heterocycloalkyl containing from four toseven atoms, including one or more heteroatoms, in the cyclic moiety ofthe heterocycloalkyl. Examples of single-ring heterocycloalkyls includeazetidinyl, oxetanyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl,dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, dihydropyranyl,piperidinyl, morpholinyl, piperazinyl, azepinyl, oxepinyl, anddiazepinyl.

The term “heteroaryl” refers to an aromatic ring structure containingthe specified number of ring atoms in which at least one of the ringatoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with theremaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A five to sixmembered heteroaryl is an aromatic ring system which has five or sixring atoms with at least one of the ring atoms being N, O or S(O)_(n).Similarly, a five to ten membered heteroaryl is an aromatic ring systemwhich has five to ten ring atoms with at least one of the ring atomsbeing N, O or S(O)_(n). A heteroaryl may be a single ring or 2 fusedrings.

Examples of heteroaryl substituents include six membered ringsubstituents such as pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl;five membered ring substituents such as triazolyl, imidazolyl, furanyl,thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-,1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ringsubstituents such as benzothiofuranyl, isobenzothiofuranyl,benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-memberedfused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,and 1,4-benzoxazinyl. In a group that has a heteroaryl substituent, thering atom of the heteroaryl substituent that is bound to the group maybe the at least one heteroatom, or it may be a ring carbon atom, wherethe ring carbon atom may be in the same ring as the at least oneheteroatom or where the ring carbon atom may be in a different ring fromthe at least one heteroatom. Similarly, if the heteroaryl substituent isin turn substituted with a group or substituent, the group orsubstituent may be bound to the at least one heteroatom, or it may bebound to a ring carbon atom, where the ring carbon atom may be in thesame ring as the at least one heteroatom or where the ring carbon atommay be in a different ring from the at least one heteroatom. The term“heteroaryl” also includes pyridinyl N-oxides and groups containing apyridine N-oxide ring. Examples of 2-fused-ring heteroaryls includeindolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl (including pyrido[3, 4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4, 3-5]-pyridinyl), pyrrolopyridinyl,pyrazolopyridinyl and imidazothiazolyl and pteridinyl.

Other examples of fused-ring heteroaryls include benzo-fused heteroarylssuch as indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl(including quinolinyl or isoquinolinyl), phthalazinyl, quinoxalinyl,benzodiazinyl (including cinnolinyl or quinazolinyl), benzopyranyl,benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl,benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl,benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl. Theforegoing groups, as derived from the groups listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl (N-attached) or imidazol-2-yl (C-attached).

The term “halo” or “halogen” refers to fluoro (which may be depicted as—F), chloro (which may be depicted as —Cl), bromo (which may be depictedas —Br), or iodo (which may be depicted as —I).

The term “hydrogen” refers to a hydrogen substituent, and may bedepicted as —H.

The term “hydroxy” or “hydroxyl” refers to —OH. Compounds bearing acarbon to which one or more hydroxyl substituents are attached include,for example, alcohols, enols and phenol.

The term “phenyl” refers to an aromatic ring having the radical —CeHs,derived from benzene by removal of a hydrogen atom. Phenyl may beoptionally fused with a five or six membered cycloalkyi orheterocycloalkyl ring to form bicyclic compounds. Examples of thesebicyclic compounds include 1,2,3,4-tetrahydronaphthalene,2,3-dihydrobenzo[1,4]oxazine, 2,3-dihydro-1H-indene, isoindoline, and2,3-dihydrobenzo[1,4]dioxine.

If substituents are described as being “independently selected” from agroup, each instance of a substituent is selected independent of theother. Each substituent therefore may be identical to or different fromthe other substituent(s).

As used herein, the term “formula I”, “formula (I)”, “Formula (I)”, or“Formula I” may be referred to as a “compound(s) of the invention”. Suchterms are also defined to include all forms of the compound of formulaI, including hydrates, solvates, isomers, crystalline and noncrystallineforms, isomorphs, polymorphs, and metabolites thereof. For example, thecompounds of the invention, or pharmaceutically acceptable saltsthereof, may exist in unsolvated and solvated forms. When the solvent orwater is tightly bound, the complex will have a well-definedstoichiometry independent of humidity. When, however, the solvent orwater is weakly bound, as in channel solvates and hygroscopic compounds,the water/solvent content will be dependent on humidity and dryingconditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may exist as clathrates or othercomplexes. Included within the scope of the invention are complexes suchas clathrates, drug-host inclusion complexes wherein the drug and hostare present in stoichiometric or non-stoichiometric amounts. Alsoincluded are complexes of the compounds of the invention containing twoor more organic and/or inorganic components which may be instoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. Fora review of suchcomplexes, see J. Pharm. Sci., 64 (8), 1269-1288, Haleblian, J. K.(August 1975).

The compounds of the invention may have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of Formula I maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof Formula I can exist as enantiomers and diastereomers or as racematesand mixtures thereof. The use of a solid line to depict bonds to one ormore asymmetric carbon atoms in a compound of Formula I and the use of asolid or dotted wedge to depict bonds to other asymmetric carbon atomsin the same compound is meant to indicate that a mixture ofdiastereomers is present.

Stereoisomers of Formula I include cis and trans isomers, opticalisomers such as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, conformational isomers, and tautomers of thecompounds of the invention, including compounds exhibiting more than onetype of isomerism; and mixtures thereof (such as racemates anddiastereomeric pairs). Also included are acid addition or base additionsalts wherein the counterion is optically active, for example, D-lactateor L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The present invention comprises the tautomeric forms of compounds of theinvention. Where structural isomers are interconvertible via a lowenergy barrier, tautomeric isomerism (‘tautomerism’) can occur. This cantake the form of proton tautomerism in compounds of the inventioncontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism. The various ratios of the tautomers in solid and liquid formare dependent on the various substituents on the molecule as well as theparticular crystallization technique used to isolate a compound.

Examples of types of potential tautomerisms shown by the compounds ofthe invention include hydroxypyridine ⇔ pyridone; amide ⇔ hydroxyl-imineand keto ⇔ enol tautomersims:

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound. Where a salt is intended to be administered to a patient (asopposed to, for example, being used in an in vitro context), the saltpreferably is pharmaceutically acceptable. The term “pharmaceuticallyacceptable salt” refers to a salt prepared by combining a compound offormula I with an acid whose anion, or a base whose cation, is generallyconsidered suitable for human consumption. Pharmaceutically acceptablesalts are particularly useful as products of the methods of the presentinvention because of their greater aqueous solubility relative to theparent compound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts”. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude, for example, aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids.Specific examples of suitable organic acids include acetate,trifluoroacetate, formate, propionate, succinate, glycolate, gluconate,digluconate, lactate, malate, tartaric acid, citrate, ascorbate,glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate,benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate,phenylacetate, mandelate, embonate (pamoate), methanesulfonate,ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate,2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate,P-hydroxybutyrate, galactarate, galacturonate, adipate, alginate,butyrate, camphorate, camphorsulfonate, cyclopentanepropionate,dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate,hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate,pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, andundecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, i.e., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups may be quaternized with agents such as loweralkyl (C₁-C₆) halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides), arylalkylhalides (e.g., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulfate and hemicalcium salts.

Also within the scope of the present invention are so-called “prodrugs”of the compound of the invention. Thus, certain derivatives of thecompound of the invention which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into the compound of the invention having the desiredactivity, for example, by hydrolytic cleavage. Such derivatives arereferred to as “prodrugs”. Further information on the use of prodrugsmay be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACSSymposium Series (T. Higuchi and V. Stella, Eds.), American ChemicalSociety, 1975 Washington, D.C. and “Bioreversible Carriers in DrugDesign”, Pergamon Press, 1987 (E. B. Roche, Ed.) American PharmaceuticalAssociation. Prodrugs in accordance with the invention can, for example,be produced by replacing appropriate functionalities present in thecompounds of any of formula I with certain moieties known to thoseskilled in the art as “pro-moieties” as described, for example, inBundgaard, H. 1985. Design of Prodrugs. New York: Elsevier.

The present invention also includes isotopically labeled compounds,which are identical to those recited in formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C,¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certain isotopicallylabeled compounds of the present invention, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds of formula I of this invention and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples and Preparations below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

DETAILED DESCRIPTION OF THE INVENTION

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject. The compoundsof the invention may be administered orally. Oral administration mayinvolve swallowing, so that the compound enters the gastrointestinaltract, or buccal or sublingual administration may be employed, by whichthe compound enters the blood stream directly from the mouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques. In another embodiment,the compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally ortransdermally. In anotherembodiment, the compounds of the invention can also be administeredintranasally or by inhalation. In another embodiment, the compounds ofthe invention may be administered rectally or vaginally. In anotherembodiment, the compounds of the invention may also be administereddirectly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing from about 0.01 mg to about 500 mg of the activeingredient, or in another embodiment, from about 1 mg to about 100 mg ofactive ingredient. Intravenously, doses may range from about 0.1 toabout 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compound ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention.

In another embodiment, the oral administration may be in a powder orgranule form. In another embodiment, the oral administration may be in aspray-dried dispersion. In another embodiment, the oral dose form issub-lingual, such as, for example, a lozenge. In such solid dosageforms, the compounds of formula I are ordinarily combined with one ormore adjuvants. Such capsules or tablets may contain acontrolled-release formulation. In the case of capsules, tablets, andpills, the dosage forms also may comprise buffering agents or may beprepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (e.g., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing or wetting agents and suspending agents.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety.

Typical formulations for this purpose include gels, hydrogels, lotions,solutions, creams, ointments, dusting powders, dressings, foams, films,skin patches, wafers, implants, sponges, fibers, bandages andmicroemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated; see, for example, J. Pharm. Sci., 88(10), 955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g., absorbable gel sponges,collagen) and nonbiodegradable (e.g., silicone) implants, wafers, lensesand particulate or vesicular systems, such as niosomes or liposomes. Apolymer such as cross-linked polyacrylic acid, polyvinyl alcohol,hyaluronic acid, a cellulosic polymer, for example,(hydroxypropyl)methyl cellulose, hydroxyethyl cellulose, or methylcellulose, or heteropolysaccharide polymer, for example, gelan gum, maybe incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray, delivered from apressurized container or a nebulizer with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Lieberman et al., Eds., Pharmaceutical DosageForms, Marcel Dekker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3rd ed.), American PharmaceuticalAssociation, Washington, 2000.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially.

Two or more compounds may be administered simultaneously, concurrentlyor sequentially. Additionally, simultaneous administration may becarried out by mixing the compounds prior to administration or byadministering the compounds at the same point in time but at differentanatomic sites or using different routes of administration.

The phrases “concurrent administration”, “co-administration”,“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of a CFTRpotentiator compound as provided in Formula I and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of Formula I or a pharmaceutically acceptable salt of thecompound; (b) a second pharmaceutically active agent; (c) optionally athird pharmaceutically active agent; and (d) a pharmaceuticallyacceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of Formula I, depending on the disease,disorder, or condition to be treated. For example, a pharmaceuticalcomposition for use in treating Cystic Fibrosis may comprise a compoundof Formula I or a pharmaceutically acceptable salt thereof, togetherwith one or more agents such as a CFTR modulator, for example anotherCFTR potentiator, a CFTR corrector, including a CAL (CFTR-associatedligand) inhibitor, a CFTR Production corrector or read-through agent, aCFTR stabilizer, including a CFTR-Dab2 (Disabled homolog 2) inhibitor,or a CFTR amplifier; an epithelial sodium channel (ENaC)inhibitor/blocker; an oligonucleotide patch; an autophagy inducer; aproteostasis modulator, including a histone deacetylase (HDAC)inhibitor; or supportive therapies such as a mucolytic agent, abronchodilator, an antibiotic, an anti-infective agent, ananti-inflammatory agent, an anticholinergic, a mast cell stabilizer, acorticosteroid, a nutritional agent, or an enzyme replacement.

A combination can include more than one agent from a particular class ofagents; for example, a combination of a compound of Formula I with twoor more CFTR correctors. Pharmaceutically active agents that may be usedin combination with the compounds of Formula I and compositions thereofinclude, without limitation:

-   -   (i) CFTR potentiators, such as VX-770 (ivacaftor), GLPG-1837,        GLPG-2451, QBW-251, GLPG-3067, FDL-129, CTP-656, FDL-176,        PTI-P271, and CTP-656;    -   (ii) CFTR correctors, such as VX-809 (lumacaftor), VX-661        (tezacaftor), VX-983 VX-152, VX-440, VX-659, GLPG-2737, P247-A,        FDL-169, FDL-304, GLPG-2222, GLPG-2665, GLPG-2851, PTI-C1811,        NU-001, and NU-002    -   (iii) CFTR amplifiers, such as PTI-428 and PTI-130    -   (iv) Read-through agents, such as ataluren    -   (v) CFTR stabilizers, such as N91115 (cavosonstat, an        S-nitrosoglutathione reductase “GSNOR” inhibitor)    -   (vi) Epithelial sodium channel (ENaC) inhibitors, such as        SPX-101, QBW-276 and VX-371;    -   (vii) Oligonucleotide patches, such as QR-010    -   (viii) Autophagy inducers, such as CX-4945, the combination of        cysteamine and epigallocatechin gallate (EGCG), cystamine, and        rapamycin    -   (ix) Proteostasis modulators, such as histone deacetylase (HDAC)        inhibitors including 4-phenylbutyrate (4-PBA)    -   (x) Supportive therapies, such as albuterol, salmeterol,        ciprofloxacin, fluticasone, prednisone, ipratropium bromide,        lipase, protease, and amylase

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention optionally in combination withone or more additional therapeutic agents and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention. In another embodiment, the kit of the present inventioncomprises one or more compounds of the invention optionally with one ormore additional therapeutic agents.

General Synthetic Schemes

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of Formula (I). It will be further appreciated that it may benecessary or desirable to carry out the transformations in a differentorder from that described in the schemes, or to modify one or more ofthe transformations, to provide the desired compound of the invention.

All of the derivatives of Formula I can be prepared by the proceduresdescribed in the general methods presented below or by routinemodifications thereof. The present invention also encompasses any one ormore of these processes for preparing the derivatives of Formula I, inaddition to any novel intermediates used therein. The person skilled inthe art will appreciate that the following reactions may be heatedthermally or under microwave irradiation.

The routes below, including those mentioned in the Examples andPreparations, illustrate methods of synthesising compounds of Formula I.The skilled person will appreciate that the compounds of the invention,and intermediates thereto, could be made by methods other than thosespecifically described herein, for example by adaptation of the methodsdescribed herein, for example by methods known in the art. Suitableguides to synthesis, functional group interconversions, use ofprotecting groups, etc., are for example: “Comprehensive OrganicTransformations” by RC Larock, VCH Publishers Inc. (1989); AdvancedOrganic Chemistry” by J. March, Wiley Interscience (1985); “DesigningOrganic Synthesis” by S Warren, Wiley Interscience (1978); “OrganicSynthesis—The Disconnection Approach” by S Warren, Wiley Interscience(1982); “Guidebook to Organic Synthesis” by R K Mackie and D M Smith,Longman (1982); “Protective Groups in Organic Synthesis” by T W Greeneand PGM Wuts, John Wiley and Sons, Inc. (1999); and “Protecting Groups”by P J Kocienski, Georg Thieme Verlag (1994); and any updated versionsof said standard works.

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used in aconventional manner. See, for example, those described in ‘Greene'sProtective Groups in Organic Synthesis’ by Theodora W Greene and Peter GM Wuts, fifth edition, (John Wiley and Sons, 2014), incorporated hereinby reference, which also describes methods for the removal of suchgroups.

In the general synthetic methods below, unless otherwise specified, thesubstituents are as defined above with reference to the compounds ofFormula (I) above. Where ratios of solvents are given, the ratios are byvolume unless otherwise specified.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of Formula I.

According to a first process, compounds of Formula (IC) (where R²═CN)may be prepared from compounds of Formulae (IA) and (IB) as illustratedby Scheme 1.

In Scheme 1, compound of the Formula (IA) is converted to a compound ofFormula (IB) wherein Hal is chloro, bromo or iodo (preferably bromo) bytreatment with a suitable halogenating agent such as N-(Hal)succinimide,preferably NBS, in a suitable solvent, such as DCM or DMF at anappropriate temperature such as 0° C. A skilled person also knows thatalternative methods for specifically introducing a suitable halogengroup such as Br are achievable using alternative reagents, solvents andtemperatures. A compound of Formula (IB) is converted into a compound ofFormula (IC) by treatment with a suitable organometallic source ofcyanide such as Zn(CN)₂ or CuCN in the presence of a suitable catalyst,such as Pd(dppf)Cl₂ (or Pd₂(dba)₃ plus dppf) in a suitable solvent, suchas DMF or NMP at a suitable temperature. A skilled person also knowsthat alternative organometallic coupling strategies can be usedinvolving alternative coupling partners, metals and solventcombinations. It is well understood by a skilled person that a compoundof the Formula (IB) is prepared and isolated as described above orprepared in situ without isolation in a sequential reaction strategyleading to a compound of Formula (IC). In the case of compounds ofFormula (IA), (IB) or (IC) where R^(1a) and R^(1b) are different groups(for example where R^(1a) is (C₁-C₃)alkyl and R^(1b) is H) leading tothe presence of a chiral center it is well understood by a skilledperson that the individual enantiomers can be obtained using a suitableseparation method such as SFC chromatography to afford both the (+) and(−)-enantiomers of compounds of Formula (IA), (IB) or (IC). It is wellunderstood by a skilled person that an individual enantiomer of acompound of the Formula (IA), (IB) or (IC) is prepared and isolated asdescribed above or isolated using an alternative separation techniquesuch as HPLC using a suitable chiral stationary phase eluting with asuitable mobile phase as determined to be necessary to isolate therequired enantiomers.

According to a second process, compounds of Formula (ID) (where R²═H,CN, (C₁-C₃)alkyl) may be prepared from compounds of Formula (II) and(III) as illustrated by Scheme 2.

In Scheme 2, compounds of Formula (ID), wherein Hal is chloro, bromo oriodo, may be prepared from compounds of Formula (II) and (III) using asuitable organometallic cross-coupling reaction such as Suzukicross-coupling reaction preceded if necessary by a boronic esterformation. Typical Suzuki cross-coupling conditions comprise a palladiumcatalyst containing suitable phosphine ligands, in the presence of aninorganic base, in aqueous dioxane or methanol, at elevated temperatureseither thermally or under microwave irradiation. Preferred conditionscomprise Pd(OAc)₂, Pd(dppf)Cl₂ or Pd(PPh₃)₄ with either sodium, cesiumor potassium carbonate in aqueous dioxane or methanol at from roomtemperature to 120° C. Typical boronic ester formation conditionscomprise Pd(dppf)Cl₂ and potassium acetate with bispinacolatodiboronwith compounds of Formula W-Q (where Q=chloro, bromo or iodo) in dioxaneat reflux. Alternatively, compounds of the Formula (ID) may be preparedby alternative cross-coupling strategies such as theMigita-Kosugi-Stille coupling using a compound of Formula (II) andFormula (III) (where Q=SnR^(y) ₃ and R^(y) is alkyl (e.g., butyl))preceded if necessary by an arylstannane formation reaction.

Compounds of Formula (ID) may also be prepared from compounds of Formula(II) using a suitable zinc reagent such as compounds of Formula (III)(where Q=ZnBr) with a palladium catalyst such as Pd(OAc)₂ in thepresence of suitable phosphine ligands such as s-Phos, in a suitablesolvent such as THF, at a suitable temperature such as room temperature.

Compounds of Formula (ID) may also be prepared by a suitable C—Hactivation strategy using a compound of Formula (II) and a compound ofFormula (III) (where Q=H) in the presence of a palladium catalyst in thepresence of an inorganic base, at a suitable temperature such as 50° C.Typical conditions comprise Pd(OAc)₂, with sodium acetate and BU₄NCl. Askilled person will know that alternative conditions are available andcan be selected depending on the reactivity of the substrates. Compoundsof Formula (III) may be obtained commercially or by analogy with themethods described herein.

According to a third process, compounds of Formula (IE) may be preparedfrom compounds of Formula (IVa), (V), (VI) and (VII) as illustrated byScheme 3.

In Scheme 3, compounds of Formula (IE) (where R² and R³═H) may beprepared from compounds of Formula (VII) by the reaction of aqueousammonium hydroxide solution in a suitable solvent such as MeOH at asuitable temperature such as 70° C. for an appropriate time such as 18hours in a sealed tube. Compounds of Formula (VII) may be prepared by asuitable alkylation reaction with compounds of Formula (V) and (VI) (LGis a suitable leaving group such as a halogen in particular a chlorineatom or a mesylate) in the presence of a suitable base such as CS₂CO₃ ina suitable solvent such as DMF at a suitable temperature such as 80° C.Compounds of Formula (VI) may be obtained commercially or by analogywith the methods described herein. Compounds of Formula (V) may beprepared from compounds of Formula (IVa) by the reaction with DMF-DMA ata suitable temperature from room temperature to 100° C. preferably at50° C.

Compounds of Formula (IV) may be prepared from compounds of Formulae(III), (VIII), (IX), (X), (XI) and (XII) as illustrated by Scheme 4.

In Scheme 4 Hal is chloro, bromo or iodo; PG is a suitable protectinggroup understood by a skilled person; and the compound of Formula III(W-Q) is as defined in Scheme 2. Compounds of Formula (IX) may beprepared by halogenation of compounds of Formula (VIII). Compounds ofFormula (IX) may be prepared by treatment of compounds of Formula (VIII)with a suitable halogenating agent such as N-(Hal)succinimide,preferably NIS, in a suitable solvent, such as DCM or DMF at anappropriate temperature such as 0° C. A skilled person also knows thatalternative methods for specifically introducing a suitable halogengroup such as iodo are achievable using alternative reagents, solventsand temperatures. A skilled person also knows that alternativehalogenation strategies can be used involving alternative sources ofhalogen, solvent and temperature combinations. It is well understood bya skilled person that a compound of the Formula (IX) is prepared andisolated as described above or prepared in situ without isolation in asequential reaction strategy leading to a compound of Formula (X).Compounds of the Formula (X) can be prepared from compounds of Formula(IX) using a suitable protecting group such astrimethylsilylethoxymethyl (SEM) by the reaction of SEMCI with compoundsof Formula (IX) and a suitable base such as NaH in a suitable solventsuch as THF and at a suitable temperature such as from 0° C. to roomtemperature. Compounds of the Formula (XI) (where R³ is H) may beprepared from compounds of Formula (X) by the reaction of aqueousammonium hydroxide solution in a suitable solvent such as MeOH at asuitable temperature such as 70° C. for an appropriate time such as 18hours in a sealed tube. Additionally, compounds of the Formula (XI)(where R³ is (C₁-C₃)alkyl) may be prepared from compounds of Formula (X)by the reaction with an appropriate primary amine such as methylamine ina suitable solvent such as THF at a suitable temperature such as 70° C.in a sealed tube. Compounds of the Formula (XII) may be prepared fromcompounds of Formulae (XI) and (III) using a suitable organometalliccross-coupling reaction such as Suzuki cross-coupling reaction precededif necessary by a boronic ester formation reaction, as described inScheme 2. Typical boronic ester formation conditions comprisePd(dppf)Cl₂ and potassium acetate with bispinacolatodiboron withcompounds of Formula (III) (where Q=Hal) in dioxane at reflux.Alternatively, compounds of the Formula (XII) may be prepared byalternative cross-coupling strategies such as the Migita-Kosugi-Stillecoupling using a compound of Formula (XII) and Formula (III) (whereQ=SnR^(y) ₃) preceded if necessary by an arylstannane formationreaction. Compounds of the Formula (IV) may be prepared from compoundsof Formula (XII) (where PG=SEM) using a suitable deprotection methodsuch as neat TFA or optionally in a suitable solvent such as DCM at asuitable temperature such as 0° C. to room temperature. It is wellunderstood by a skilled person that alternative methods of deprotectionmay be used such as TBAF in a suitable solvent such as THF at a suitabletemperature such as 0° C. to 70° C.

Compounds of Formula (II) may be prepared from compounds of Formula(VI), (IX) and (XIII) wherein Hal is chloro, bromo or iodo asillustrated by Scheme 5.

Compounds of Formula (XIII) may be prepared from compounds of Formula(IX) and Formula (VI) (LG is a suitable leaving group such as a halogenin particular a chlorine atom or a mesylate) in the presence of asuitable base such as Cs₂CO₃ in a suitable solvent such as DMF at asuitable temperature such as 80° C. It is well understood by a skilledperson that alternative methods to prepared compounds of Formula (XIII)are available such as a Mitsonobu reaction with compounds of Formulae(IX) and (VI) (where LG=OH) using a suitable alcohol activating reagentsuch as DIAD and PPh₃ in a suitable solvent such as THF at a suitabletemperature such as 0° C. to room temperature. Compounds of the Formula(II) (where R³ is H) may be prepared from compounds of Formula (XIII) bythe reaction of aqueous ammonium hydroxide solution in a suitablesolvent such as MeOH at a suitable temperature such as 70° C. for anappropriate time such as 18 hours in a sealed tube. Additionally,compounds of the Formula (II) (where R³ is (C1-C3)alkyl) may be preparedfrom compounds of Formula (XIII) by the reaction with an appropriateprimary amine such as methylamine in a suitable solvent such as THF at asuitable temperature such as 70° C. in a sealed tube.

Compounds of Formula (IIA) (where Y=1,2,3-triazole) may be prepared fromcompound of the Formula (IXa), (XIV), (XV), (XVI) and (XVII) wherein Halis chloro, bromo or iodo as illustrated in Scheme 6.

Compounds of Formula (IIA) may be prepared from compounds of Formula(XV) and (XVII) using a suitable 1,3-dipolar cycloaddition reaction suchas a copper catalysed Click reaction using catalyst such as CuI in asuitable solvent such as toluene and tBuOH and a suitable base such asDIPEA and at a suitable temperature such as 0° C. to room temperature.It is well understood by a skilled person that alternative methods ofheterocycle formation are also possible. Compounds of Formula (XV)(where R³ is H) may be prepared from compounds of Formula (XIV) by thereaction of aqueous ammonium hydroxide solution in a suitable solventsuch as MeOH at a suitable temperature such as 70° C. for an appropriatetime such as 18 hours in a sealed tube. Additionally, compounds of theFormula (XV) (where R³ is (C₁-C₃)alkyl) may be prepared from compoundsof Formula (XIV) by the reaction with an appropriate primary amine suchas methylamine in a suitable solvent such as THF at a suitabletemperature such as 70° C. in a sealed tube. Compounds of Formula (XIV)may be prepared from compounds of Formula (IXa) and Formula (XVI) (LG isa suitable leaving group such as a halogen in particular a chlorine atomor a mesylate) in the presence of a suitable base such as CS₂CO₃ in asuitable solvent such as DM F at a suitable temperature such as 80° C.,preceded if necessary by a suitable functional group inter-conversionreaction such as conversion of an alcohol (LG=OH) to a chloride (LG=Cl)using methods known to a skilled person.

Compounds of Formula (Xi) (where R²═(C₁-C₃)alkyl, PG=SEM and Hal ischloro, bromo or iodo) may be prepared from compounds of the Formula(X), (where R²═H and Hal is chloro, bromo or iodo) as illustrated inScheme 7.

Compounds of Formula (Xi) (where R²═(C₁-C₃)alkyl and PG=SEM) may beprepared from Compounds of Formula (X) (where R²═H and PG=SEM) andcompounds of Formula (XVIII) using a suitable aprotic base such as LDAat a suitable temperature such as −78° C. in a suitable solvent such asTHF. It is well understood by a skilled person that alternative methodsof selective ligand-directed deprotonation-alkylation may be used withalternative PG, base and alkylating group combinations in a suitablesolvent and at a suitable temperature.

Compounds of Formula (IF) may be prepared from compounds of Formula(III), (XVII), (XIV), (XIX), (XX), (XXI), and (XXII), wherein Q is Haland Hal is chloro, bromo or iodo, as illustrated in Scheme 8.

Compounds of Formula (IF) may be prepared from compounds of the Formula(XXI) by a suitable halogen displacement by analogy with Schemes 4, 5and 6. Compounds of the Formula (XXI) may be prepared from compounds ofFormula (XX) and Formula (III) (where Q=Hal) by a suitableorganometallic cross-coupling reaction such as a Suzuki cross-couplingreaction as described in Scheme 8. Typical Suzuki cross-couplingconditions comprise a palladium catalyst containing suitable phosphineligands, in the presence of an inorganic base, in aqueous dioxane ormethanol, at elevated temperatures either thermally or under microwaveirradiation. Preferred conditions comprise Pd(OAc)₂, Pd(dppf)Cl₂ orPd(PPh₃)₄ with either sodium, cesium or potassium carbonate in aqueousdioxane or methanol at room temperature to 120° C. Compounds of theFormula (XX) may be produced from compounds of Formula (XIX) and (XXII)by a boronic ester formation reaction. Typical boronic ester formationconditions comprise Pd(dppf)Cl₂ and potassium acetate withbispinacolatodiboron in dioxane at reflux. Compounds of Formula (XIX)may be prepared from compounds of Formula (XIV) and (XVII) using asuitable 1,3-dipolar cycloaddition reaction such as a copper catalysedClick reaction using catalyst such as CuI in a suitable solvent such astoluene and tBuOH and a suitable base such as DIPEA and at a suitabletemperature such as 0° C. to room temperature. It is well understood bya skilled person that alternative methods of heterocycle formation arealso possible.

Compounds of Formula (MB) may be prepared from compounds of the Formulae(XV) and (XXIII) and wherein Hal is chloro, bromo or iodo as illustratedin Scheme 9.

Compounds of Formula (IIB) may be prepared from compounds of the Formula(XV) and (XXIII) by a suitable 1,3-dipolar cycloaddition in a suitablesolvent such as toluene in the presence of a suitable base such as Et₃Nat a suitable temperature such a 0° C. to 60° C. for an appropriate timesuch as 16 hr.

Compounds of Formula (VI) may be prepared from compounds of Formula(XXXI), (XXIV), (XXV), and (XXVI), as illustrated in Scheme 10 whereinHal is chloro, bromo or iodo; M is a suitable metal.

Compounds of Formula (VI) (wherein LG=Cl) may be prepared from compoundsof Formulae (XXVI) by a suitable chlorination such as SOCl₂ either neator in a suitable solvent at a suitable temperature. Compounds of Formula(XXVI) may be prepared from compounds of Formula (XXIV) and (XXV) by asuitable organometallic addition reaction using a suitable metal (M)such as Mg in a suitable solvent such as THF at a suitable temperaturesuch a 0° C. to room temperature. Compounds of Formula (XXIV) may beprepared from a suitable oxidation of compounds of Formula (XXXI) usinga suitable reagent such as MnO₂ in a suitable solvent. A skilled personalso knows that alternative oxidation strategies can be used involvingalternative oxidants and solvent combinations.

Compounds of Formula (XXXI) may alternatively be prepared from compoundsof Formulae (XXVII) as illustrated in Scheme 11 wherein Hal is chloro,bromo or iodo; M is a suitable metal.

Compounds of Formula (XXXI) may be prepared from compounds of Formula(XXVII) and a suitable organometallic compound of Formula (XXVIII) in asuitable aprotic solvent such as THF at a suitable temperature such as0° C. to reflux. A skilled person appreciates that alternative methodsare available to add an alkyl group to an aldehyde using differentorganometallic nucleophiles.

Compounds of Formula (XXIV) may be alternatively prepared from compoundsof Formulae (XXVII), (XXIX) and (XXX) as illustrated in Scheme 12wherein Hal is chloro, bromo or iodo; M is a suitable metal.

Compounds of Formula (XXIV) may be prepared from compounds of theFormula (XXX) and (XXVIII) using a suitable metal (M) such as Mg in asuitable solvent such as THF at a suitable temperature such as 0° C. toroom temperature. Compounds of Formula (XXX) may be prepared fromcompounds of Formula (XXIX) and N,O-dimethylhydroxylamine in thepresence of a suitable peptide coupling reagent such as HATU and in thepresence of a suitable base such as DIPEA in a suitable solvent such asDCM at a suitable temperature such as 0° C. to room temperature.

In the case of compounds described in all of the preceding generalmethod schemes where R^(1a) and R^(1b) are different groups (for examplewhere R^(1a) is (C1-C3)alkyl and R^(1b) is H) leading to the presence ofa chiral center it is well understood by a skilled person that theindividual enantiomers can be obtained using a suitable separationmethod such as SFC chromatography to afford both the (+) and(−)-enantiomers of these compounds. It is well understood by a skilledperson that an individual enantiomer of a compound described in thepreceding general method schemes is prepared and isolated as describedabove or isolated using an alternative separation technique such as HPLCusing a suitable chiral stationary phase eluting with a suitable mobilephase as determined to be necessary to isolate the required enantiomers.

The following non-limiting Preparations and Examples illustrate thepreparation of compounds and salts of the present invention. In theExamples and Preparations that are set out below, and in theaforementioned Schemes, the following the abbreviations, definitions andanalytical procedures may be referred to. Other abbreviations common inthe art are also used. Standard IUPAC nomenclature has been used.

The following abbreviations may be used: AcOH is acetic acid; Ar isargon; aq is aqueous; Bn is benzyl; Boc is tert-butoxy carbonyl; Boc₂Ois di-tert-butyl dicarbonate; br is broad; tBu is tert-butyl; tBuOH istert-butanol; n-BuLi is n-butyl lithium; Bu₄NCl is tetrabutyl ammoniumchloride; ° C. is degrees celcius; CDCl₃ is deutero-chloroform; CS₂CO₃is cesium carbonate; CsF is cesium fluoride; CuCN is copper cyanide; CuIis copper iodide; δ is chemical shift; d is doublet; DCM isdichloromethane or methylene chloride; DIAD is diisopropylazodicarboxylate; DIPEA is N-ethyldiisopropylamine orN,N-diisopropylethylamine; DMA is N,N-dimethyl acetamide; DMAP is4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMF-DMA isN,N-dimethylformamide dimethyl acetal; DMSO is dimethyl sulfoxide; DPPAis diphenyl phosphoryl azide; Dppf is1,1′-bis(diphenylphosphino)ferrocene; EDA is ethylenediamine; Et₂O isdiethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et₃N istriethylamine; Et₃SiH is triethylsilane; g is gram; HATU is1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; HCl is hydrochloric acid; HCO₂H is formicacid; HPLC is high pressure liquid chromatography; H₂ is hydrogen; H₂Ois water; Hr is hour, hrs are hours; K₂CO₃ is potassium carbonate; KHSO₄is potassium hydrogen sulphate; KOAc is potassium acetate; K₃PO₄ ispotassium phosphate; L is liter; LCMS is liquid chromatography massspectrometry; LDA is lithium diisopropylamide LiAlH₄ or LAH is lithiumaluminium hydride; LiCl is lithium chloride; LiHMDS is lithiumbis(trimethylsilyl)amide; LiOH.H₂O is lithium hydroxide monohydrate;Li-Selectride® is lithium tri-sec-butylborohydride; m is multiplet; M ismolar; MeCN is acetonitrile; MeMgBr is methyl magnesium bromide; MeOH ismethanol; 2-MeTHF is 2-methyl tetrahydrofuran; mg is milligram; MgSO₄ ismagnesium sulphate; MHz is mega Hertz; min is minutes; mL is milliliter;mmol is millimole; MnO₂ is manganese dioxide; mol is mole; MS m/z ismass spectrum peak; MTBE is tert-butyl methyl ether; MsCl is mesylchloride; NaCN is sodium cyanide; NaBH₄ is sodium borohydride; Na₂CO₃ issodium carbonate; NaH is sodium hydride; NaHCO₃ is sodium hydrogencarbonate; NaHSO₄ is sodium hydrogen sulfate; NaHMDS is sodiumbis(trimethylsilyl)amide; NaOH is sodium hydroxide; NaOAc is sodiumacetate; NaOMe is sodium methoxide; Na₂SO₄ is sodium sulphate; Na₂S₂O₃is sodium thiosulfate; NBS is N-bromo succinimide; NCS isN-chlorosuccinimide; NH₃ is ammonia; NH₄Cl is ammonium chloride; NH₄HCO₃is ammonium hydrogen carbonate; NH₂NH₂.H₂O is hydrazine hydrate;NH₂OH.HCl is hydroxylamine hydrochloride; NH₄OH is ammonium hydroxide;NH₄OAc is ammonium acetate; Nil is nickel iodide; NIS isN-iodosuccinimide; nM is nanomolar; NMP is 1-methyl-2-pyrrolidinone; NMRis nuclear magnetic resonance; Pd/C is palladium on carbon; Pd₂(dba)₃ isTris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl₂ is[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd(OH)₂ ispalladium hydroxide; Pd(OAc)₂ is palladium acetate; PPh₃ istriphenylphosphine; Pd(PPh₃)₄ is tetrakis (triphenylphosphine)palladium(0); Pet. Ether is petroleum ether; pH is power of hydrogen; ppm isparts per million; PtO₂ is platinum (IV) oxide; q is quartet; rt is roomtemperature; RT is retention time; s is singlet; SCX is strong cationexchange; SEM-CI is 2-(trimethylsilyl)ethoxymethyl chloride; SFC issupercritical fluid chromatography; S-Phos is2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; SOCl₂ is thionylchloride; t is triplet; T3P is propylphosphonic anhydride; TBAF istert-butyl ammonium fluoride; TBD is1,5,7-triazabicyclo[4.4.0]dec-5-ene; TBME is tert-butyl dimethyl ether;TFA is trifluoroacetic acid; TFP is tri(2-furyl)phosphine; THF istetrahydrofuran; Ti(OiPr)₄ is titanium (IV) isopropoxide; TPTU is2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; μL ismicroliter; pmol is micromole; XPhos is2-dicyclohexylphosphino-2′,4′,6′-trisopropylbiphenyl; and Zn(CN)₂ isZinc cyanide. ¹H and ¹⁹F Nuclear magnetic resonance (NMR) spectra werein all cases consistent with the proposed structures. Characteristicchemical shifts (δ) are given in parts-per-million downfield fromtetramethylsilane (for ¹H-NMR) and upfield from trichloro-fluoro-methane(for ¹⁹F NMR) using conventional abbreviations for designation of majorpeaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad. The following abbreviations have been used forcommon solvents: CDCl₃, deuterochloroform; DMSO-d₆,deuterodimethylsulphoxide; and MeOH-d₄, deuteromethanol. Whereappropriate, tautomers may be recorded within the NMR data; and someexchangeable protons may not be visible.

Mass spectra, MS (m/z), were recorded using either electrosprayionisation (ESI) or atmospheric pressure chemical ionisation (APCl).

Where relevant and unless otherwise stated the m/z data provided are forisotopes ¹⁹F, ³⁵Cl, ⁷⁹Br and ¹²⁷I.

Wherein preparative TLC or silica gel chromatography have been used, oneskilled in the art may choose any combination of appropriate solvents topurify the desired compound. The following are analytical andpreparative chromatography methods used for the analysis andpurification of compounds of the invention.

Preparative SFC Methods

SFC Method A1: Column: Lux Cellulose-3, 250 mm×21.2 mm 5 u; MobilePhase—Isocratic conditions: CO₂/MeOH, 80/20 (v/v); Flow rate: 80.0mL/min.SFC Method A3: Column: Lux Cellulose-3, 250 mm×21.2 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeCN/MeOH, 50/50 (v/v); Isocratic conditions:70% A/30% B;_Flow rate: 80.0 mL/min.SFC Method A4: Column: Lux Cellulose-1, 250 mm×21.2 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeCN/MeOH, 50/50 (v/v); Isocratic conditions:75% A/25% B;_Flow rate: 80.0 mL/min.SFC Method A6: Column: Lux Cellulose-1, 250 mm×21.2 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeCN/MeOH, 50/50 (v/v); Isocratic conditions:80% A/20% B;_Flow rate: 80.0 mL/min.SFC Method A7: Column: Lux Cellulose-3, 500 mm×21.2 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 70% A/30%B;_Flow rate: 80.0 mL/min.SFC Method A9: Column: Lux Cellulose-3, 500 mm×21.2 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 90% A/10%B;_Flow rate: 80.0 mL/min.SFC Method A10: Column: Lux Cellulose-3, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions:92.5% A/7.5% B;_Flow rate: 80.0 mL/min.SFC Method B1: Column: Chiral Tech OJ-H, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 80%A/20% B;_Flow rate: 80.0 mL/min.SFC Method B3: Column: Chiral Tech OJ-H, 250 mm×50 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 85% A/15%B;_Flow rate: 250.0 mL/min.SFC Method B4: Column: Chiral Tech OJ-H, 500 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 75%A/25% B;_Flow rate: 80.0 mL/min.SFC Method C1: Column: Chiral Tech AS-H, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 75%A/25% B;_Flow rate: 80.0 mL/min.SFC Method C3: Column: Chiral Tech AS-H, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 80%A/20% B;_Flow rate: 80.0 mL/min.SFC Method C4: Column: Chiral Tech AS-H, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 85%A/15% B;_Flow rate: 80.0 mL/min.SFC Method C5: Column: Chiral Tech AS-H, 250 mm×21.2 mm 5 u; MobilePhase A: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Isocratic conditions: 85%A/15% B;_Flow rate: 80.0 mL/min.SFC Method D1: Chiral Tech IA 250 mm×21.5 mm 5 u; Mobile Phase A: CO₂;Mobile Phase B: IPA; Isocratic conditions: 60% A/40% B; Flow rate: 80.0mL/min.SFC Method D4: Chiral Tech IA 250 mm×21.5 mm 5 u; Mobile Phase A: CO₂;Mobile Phase B: MeOH; Isocratic conditions: 60% A/40% B; Flow rate: 80.0mL/min.SFC Method F1: Chiral Tech OD-H 500 mm×21.5 mm 5 u; Mobile Phase A: CO₂;Mobile Phase B: EtOH+0.2% NH₄OH; Isocratic conditions: 80% A/20% B; Flowrate: 80.0 mL/min.

Analytical SFC Methods

SFC Method A2: Column: Lux Cellulose-3, 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH; Gradient Elution (time, % A, % B): (0.00min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A, 60% B),(9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate: 3.0mL/min.SFC Method A5: Column: Lux Cellulose-1, 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH/MeCN, 50/50, (v/v); Gradient Elution (time,% A, % B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min,40% A, 60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flowrate: 3.0 mL/min.SFC Method A8: Column: Lux Cellulose-3, 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Gradient Elution (time, % A, %B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A,60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate:3.0 mL/min.SFC Method B2: Column: Chiral Tech OJ-H, 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Gradient Elution (time, % A, %B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A,60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate:3.0 mL/min.SFC Method C2: Column: Chiral Tech AS-H, 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Gradient Elution (time, % A, %B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A,60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate:3.0 mL/min.SFC Method D2: Column: Chiral Tech IA 250 mm×4.6 mm 5 u; Mobile Phase A:CO₂; Mobile Phase B: MeOH+0.2% NH₄OH; Gradient Elution (time, % A, % B):(0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A, 60%B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate: 3.0mL/min.SFC Method D3: Column: Chiral Tech IA 250 mm×4.6 mm 5 u; Mobile Phase A:CO₂; Mobile Phase B: IPA; Gradient Elution (time, % A, % B): (0.00 min,95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A, 60% B), (9.50min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate: 3.0 mL/min.SFC Method F2: Column: Chiral Tech OD-H 250 mm×4.6 mm 5 u; Mobile PhaseA: CO₂; Mobile Phase B: EtOH+0.2% NH₄OH; Gradient Elution (time, % A, %B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A,60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate:3.0 mL/min.

Preparative HPLC Methods

HPLC Method C20A: Column: CHIRALPAK IC, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH, 95/5 (v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method C20B: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH, 95/5 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C21: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/MeOH, 90/10 (v/v); Flow rate: 60 mL/min.HPLC Method C22A: Column: CHIRALPAK IC, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH/DEA, 95/5/0.1 (v/v/v); Flow rate: 30mL/min; Temperature: 35° C.HPLC Method C22B: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH/DEA, 95/5/0.1 (v/v/v); Flow rate: 30mL/min; Temperature: 35° C.HPLC Method C23A: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/EtOH, 90/10 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C23B: Column: CHIRALPAK IC, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/EtOH, 90/10 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C24A: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/EtOH, 95/5 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C24B: Column: CHIRALPAK IC, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/EtOH, 95/5 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C25A: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hex/EtOH, 70/30 (v/v); Flow rate: 60 mL/min.HPLC Method C25B: Column: CHIRALPAK IC, 2.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hex/EtOH, 70/30 (v/v); Flow rate: 9 mL/min.HPLC Method C26: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/IPA, 70/30 (v/v); Flow rate: 60 mL/min.HPLC Method C27: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOAc/DEA, 60/40/0.1 (v/v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method C28: Column: CHIRALPAK IC, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH, 85/15 (v/v); Flow rate: 30 mL/min.HPLC Method C29: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/EtOH, 80/20 (v/v); Flow rate: 60 mL/min.HPLC Method C30: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/EtOH, 75/25 (v/v); Flow rate: 60 mL/min.HPLC Method C31: Column: CHIRALPAK IC 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/EtOH/DEA, 90/10/0.1 (v/v/v); Flow rate: 60 mL/min.HPLC Method C32: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/EtOH/DEA, 85/15/0.1 (v/v/v); Flow rate: 60 mL/min.HPLC Method C33: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH, 50/50 (v/v); Flow rate: 30 mL/min.HPLC Method C34: Column: CHIRALPAK IC, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: 100% MeOH; Flow rate: 60 mL/min.HPLC Method B4: Column: CHIRALCEL OJ, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: MeOH/DEA, 90/10 (v/v); Flow rate: 30 mL/min; Temperature:35° C.HPLC Method B5: Column: CHIRALCEL OJ, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: MeOH/DEA, 100/0.1 (v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method B6: Column: CHIRALCEL OJ, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: EtOH/DEA, 100/0.1 (v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method D4: Column: CHIRALPAK AD-H, 25 cm I.D.×250 cm long;Isocratic Mobile Phase: EtOH/MeCN, 80/20 (v/v); Flow rate: 20 mL/min;Temperature: 35° C.HPLC Method D5: Column: CHIRALPAK AD-H, 2.5 cm I.D.×25 cm long;lsocratic_Mobile Phase: Hexane/EtOH, 70/30 (v/v), Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method D6: Column: CHIRALPAK AD-H, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: MeOH/MeCN, 90/10 (v/v); Flow rate: 30 mL/min.HPLC Method D7: Column: CHIRALPAK AD-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/IPA, 70/30 (v/v); Flow rate: 60 mL/min.HPLC Method E3: Column: CHIRALPAK IE, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH, 70/30 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method E4: Column: CHIRALPAK IE, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: DCM/EtOH, 95/5 (v/v); Flow rate: 55 mL/min; Temperature:35° C.HPLC Method E5: Column: CHIRALPAK IE, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH, 80/20 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method E6: Column: CHIRALPAK IE, 2.5 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH/DEA, 50/50/0.1 (v/v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method E8: Column: CHIRALPAK IE, 5.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hexane/EtOH, 50/50 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method F1: Column: CHIRALPAK AS-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/EtOH, 85/15 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method F2: Column: CHIRALPAK AS-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH, 60/40 (v/v); Flow rate of 60 mL/min;Temperature: 35° C.HPLC Method F4: Column: CHIRALPAK AS-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: EtOH/DEA, 100/0.1 (v/v); Flow rate: 60 mL/min;Temperature: 35° C.HPLC Method F7: Column: CHIRALPAK AS-H, 2.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/EtOH/DEA, 50/50/0.2 (v/v/v); Flow rate:14 mL/min; Temperature: 25° C.HPLC Method F8: Column: CHIRALPAK AS-H, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/MeOH, 95/5 (v/v); Flow rate: 30 mL/min;Temperature: 25° C.HPLC Method F9: Column: CHIRALPAK AS-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: DCM/EtOH/DEA, 90/10/0.1 (v/v/v); Flow rate: 60mL/min; Temperature: 25° C.HPLC Method G2: Column: CHIRALCEL OD-H, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/IPA, 60/40 (v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method G3: Column: CHIRALCEL OD-H, 2.0 cm I.D.×25 cm long;Isocratic Mobile Phase: IPA/TFA, 100/0.2 (v/v); Flow rate: 40 mL/min;Temperature: 40° C.HPLC Method H1: Column: CHIRALCEL OZ-H, 5.0 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/EtOH, 50/50 (v/v); Flow rate of 30mL/min; Temperature: 35° C.HPLC Method H3: Column: CHIRALCEL OZ-H, 2.5 cm I.D.×25 cm long;Isocratic Mobile Phase: Hexane/EtOH, 80/20 (v/v); Flow rate: 30 mL/min;Temperature: 35° C.HPLC Method J1: Column: Xterra RP18 (19×250 mm, 10μ); Mobile Phase A: 20mM (NH₄)₂CO₃ in water; Mobile phase B: MeCN; Gradient Elution (time, %A, % B): (0 min, 90% A, 10% B), (3 min, 75% A, 25% B), (18 min, 40% A,60% B), (19 min, 5% A, 95% B), (20 min, 5% A, 95% B); Flow rate: 16mL/min;HPLC Method K1: Column: YMC Triart C18 (20×250 mm, 5μ); Mobile Phase A:20 mM (NH₄)₂CO₃ in water; Mobile Phase B: MeCN; Gradient Elution (time,% A, % B): (0 min, 90% A, 10% B), (3 min, 75% A, 25% B), (18 min, 40% A,60% B), (19 min, 5% A, 95% B), (20 min, 5% A, 95% B); Flow rate: 16mL/min.HPLC Method L1: Column: Reprosil Gold C18 (30×100 mm, 5μ); Mobile PhaseA: 10 mM (NH₄)₂CO₃ in water; Mobile Phase B: MeCN; Gradient Elution(time, % A, % B): (0 min, 90% A, 10% B), (2 min, 60% A, 40% B), (10 min,30% A, 70% B), (11 min, 5% A, 95% B), (12 min, 5% A, 95% B); Flow rate:30 mL/min.HPLC Method L2: Column: Reprosil Gold C18 (250×20 mm, 5μ); Mobile PhaseA: 20 mM NH₄HCO₃ in water; Mobile Phase B: MeCN; Gradient Elution (time,% A, % B): (0 min, 90% A, 10% B), (3 min, 70% A, 30% B), (18 min, 40% A,60% B), (19 min, 5% A, 95% B); Flow rate: 20 mL/min.HPLC Method N1: Column: Hydrosphere C18 (250×20 mm, 5μ); Mobile Phase A:10 mM NH₄OAC in water; Mobile phase B: MeCN; Gradient Elution (time, %A, % B): (0 min, 90% A, 10% B), (3 min, 70% A, 30% B), (18 min, 40% A,60% B), (19 min, 5% A, 95% B); Flow rate: 20 mL/min.HPLC Method N2: Column: Hydrosphere C18 (250×20 mm, 5μ); Mobile Phase A:0.1% Formic acid in water; Mobile Phase B: MeCN; Gradient Elution (time,% A, % B): (0 min, 90% A, 10% B), (3 min, 80% A, 20% B), (18 min, 40% A,60% B), (19 min, 5% A, 95% B); Flow rate: 20 mL/min.HPLC Method P1: Column: Gemini C18 (100×30 mm, 5μ); Mobile Phase A: 20mM NH₄HCO₃ in water; Mobile Phase B: MeCN; Flow rate: 30 mL/min;Gradient Elution (time, % A, % B): (0 min, 90% A, 10% B), (2 min, 70% A,30% B), (10 min, 35% A, 65% B), (12 min, 5% A, 95% B).HPLC Method Q1: Column: CHIRALPAK IB, 2.0 cm I.D.×25 cm long; IsocraticMobile Phase: Hex/EtOH (50/50) (v/v); Flow rate: 14 mL/min; Temperature:25° C.

Analytical HPLC Methods

HPLC Method A [Acidic]: Column: Acquity BEH C18, 50×2.1 mm, 1.7p; Mobilephase: MeCN (0.05% TFA)-Water (0.05% TFA); Gradient: 5%-95% MeCN over 2min, hold at 95% MeCN for 0.5 min.; re-equilibrate back to 5% MeCN to2.7 min.; Flow rate: 0.8 mL/min; Temperature: 45° C.HPLC Method B1: Column: CHIRALCEL OJ-H, 0.46 cm I.D.×15 cm long;Injection: 20.0 ul; Mobile phase: MeOH/MeCN, 90/10 (v/v); Flow rate: 1.0mL/min; Wave length: UV 254 nm; Temperature: 35° C.HPLC Method B2: Column: CHIRALCEL OJ-H, 0.46 cm I.D.×15 cm long;Injection: 2.0 ul; Mobile phase: MeOH/DEA, 100/0.1 (v/v); Flow rate: 1.0mL/min; Wave length: UV 214 nm; Temperature: 35° C.HPLC Method B3: Column: CHIRALCEL OJ-H, 0.46 cm I.D.×15 cm long;Injection: 1.0 ul; Mobile phase: EtOH; Flow rate: 1.0 mL/min; Wavelength: UV 214 nm; Temperature: 35° C.HPLC Method C1: Column: CHIRALPAK IC, 0.46 cm I.D.×25 cm long; Mobilephase: DCM/EtOH, 95/5 (v/v); Flow rate: 1.0 mL/min; Wave length: UV 214nm;_Temperature: 25° C.HPLC Method C2: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: DCM/EtOH, 95/5 (v/v); Flow rate: 1.0 mL/min; Wave length: UV 214nm; Temperature: 25° C.HPLC Method C3: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long, Mobilephase: DCM/EtOH, 98/2 (v/v); Flow rate: 1.0 mL/min; Wave length: UV 254nm;_Temperature: 25° C.HPLC Method C4: Column: CHIRALPAK IC, 0.46 cm I.D.×25 cm long; Mobilephase: DCM/MeOH, 95/5 (v/v); Flow rate: 1.0 mL/min; Temperature: 25° C.HPLC Method C5: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long, 5p;Mobile phase: DCM/MeOH, 95/5 (v/v); Flow rate: 1.0 mL/min; Wave length:UV 254 nm;_Temperature: 35° C.HPLC Method C6: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: DCM/EtOH, 90/10 (v/v); Flow rate: 1.0 mL/min; Wave length: UV 254nm;_Temperature: 25° C.HPLC Method C7: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: DCM/MeOH/DEA, 95/5/0.1 (v/v/v); Flow rate: 1.0 mL/min; Wavelength: UV214 nm; Temperature: 35° C.HPLC Method C8: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: MeOH; Flow rate: 1.0 mL/min; Wave length: UV 214 nm; Temperature:35° C.HPLC Method C9: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: DCM/MeOH, 90/10 (v/v); Flow rate: 1.0 mL/min; Wave length: UV 254nm;_Temperature: 35° C.HPLC Method C10: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: DCM/EtOH/DEA, 90/10/0.1 (v/v); Flow rate: 1.0 mL/min; Wavelength: UV254 nm; Temperature: 25° C.HPLC Method C11: Column: CHIRALPAK IC, 0.46 cm I.D.×25 cm long; Mobilephase: Hexane/EtOH, 70/30 (v/v); Flow rate: 1.0 mL/min; Wave length: UV214 nm;_Temperature: 35° C.HPLC Method C12: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/EtOH, 85/15 (v/v); Flow rate: 1.0 mL/min; Wave length: UV214 nm;_Temperature: 35° C.HPLC Method C13: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/EtOAC/DEA, 60/40/0.1 (v/v/v); Flow rate: 1.0 mL/min; Wavelength: UV 214 nm; Temperature: 35° C.HPLC Method C14: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/EtOH, 80/20 (v/v/v); Flow rate: 1.0 mL/min; Wave length:UV 214 nm; Temperature: 35° C.HPLC Method C15: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/EtOH/DEA, 50/50/0.1 (v/v/v);_Flow rate: 1.0 mL/min;_Wavelength: UV 214 nm; Temperature: 35° C.HPLC Method C16: Column: CHIRALPAK IC, 0.46 cm I.D.×15 cm long; Mobilephase: MeOH/MeCN, 90/10 (v/v); Flow rate: 1.0 mL/min; Wave length: UV214 nm;_Temperature: 35° C.HPLC Method C16A: Column: CHIRALPAK IC, 0.46 cm I.D.×25 cm long; Mobilephase: DCM/EtOAc/DEA, 85/15/0.1 (v/v/v); Flow rate: 1.0 mL/min; Wavelength: UV 254 nm; Temperature: 35° C.HPLC Method C17: Column: CHIRALPAK IC, 0.46 cm I.D.×25 cm long; Mobilephase: Hexane/EtOH, 50/50 (v/v); Flow rate: 1.0 mL/min; Wave length: UV254 nm;_Temperature: 35° C.HPLC Method D1: Column: CHIRALPAK AD-H, 0.46 cm I.D.×15 cm long; Mobilephase EtOH/MeCN, 80/20 (v/v); Flow rate 1.0 mL/min; Wave length UV 214nm; Temperature: 35° C.HPLC Method D2: Column: CHIRALPAK AD-H, 0.46 cm ID×15 cm long;_MobilePhase: Hexane/EtOH, 70/30 (v/v); Flow rate: 1.0 mL/min; Wavelength: UV214 nm;_Temperature: 35° C.HPLC Method D3: Column: CHIRALPAK AD-H, 0.46 cm ID×15 cm long; MobilePhase: Hexane/EtOH, 60/40 (v/v); Flow rate: 1.0 mL/min; Wavelength: UV214 nm;_Temperature: 25° C.HPLC Method E1: Column: CHIRALPAK IE, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/EtOH, 70/30 (v/v); Flow rate: 1.0 mL/min; Wave length: UV214 nm; Temperature: 25° C.HPLC Method E2: Column: CHIRALPAK IE, 0.46 cm I.D.×15 cm long; Mobilephase: Hexane/IPA, 70/30 (v/v); Flow rate: 1.0 mL/min; Wave length: UV254 nm; Temperature: 35° C.HPLC Method E7: Column: CHIRALPAK IE, 0.46 cm I.D.×25 cm long; Mobilephase: Hexane/EtOH/DEA, 50/50/0.1 (v/v/v); Flow rate: 1.0 mL/min; Wavelength: UV 254 nm; Temperature: 35° C.HPLC Method F3: Column: CHIRALPAK AS-H, 0.46 cm×15 cm long;_MobilePhase: Hexane/EtOH, 85/15 (v/v); Flow rate: 1.0 mL/min; Wavelength: 254nm;_Temperature: 35° C.HPLC Method F5: Column: CHIRALPAK AS-H, 0.46 cm×15 cm long; MobilePhase: MeOH; Flow rate: 1.0 mL/min; Wavelength: 254 nm; Temperature: 35°C.HPLC Method G1: Column: CHIRALPAK OD-H, 0.46 cm×15 cm long; MobilePhase: Hexane/IPA, 60/40 (v/v); Flow rate: 1.0 mL/min; Wavelength: 214nm; Temperature: 25° C.HPLC Method H2: Column: CHIRALCEL OZ-H, 0.46 cm×15 cm long; MobilePhase: Hexane/EtOH, 50/50 (v/v); Flow rate: 1.0 mL/min; Wavelength: 214nm;_Temperature: 25° C.HPLC Method M1: Column: RESTEKC18 (30×2.1) 3 u; Temperature: 50° C.;Flow rate: 1.5 mL/min; Injection volume: 3 ul; Mobile Phase A: 0.05%HCOOH in water; Mobile Phase B: MeCN; Gradient Elution (time, % A, % B):(0 min, 98% A, 2% B), (0.75 min, 98% A, 2% B), (1.0 min, 90% A, 10% B),(2.0 min, 2% A, 98% B), (2.25 min, 2% A, 98% B).

Preparation of Intermediates Preparation 1:N′-(7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

Step 1: To a solution of(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)methanol (Preparation 102, 0.698g, 3.324 mmol) in DCM (15 mL) was added SOCl₂ (0.48 mL, 6.648 mmol) at0° C. under N₂. The mixture was stirred at rt for 1 hr, evaporated todryness in vacuo to afford4-(chloromethyl)-1-(2,4-difluorophenyl)-1H-pyrazole as a brown oil (0.74g, yield 93%). This material was used in the following reaction withoutfurther purification.

Step 2: To a solution ofN,N-dimethyl-N′-{5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}formimidamide(Preparation 17, 0.87 g, 2.591 mmol) in DMF (15 mL) was added Cs₂CO₃(1.69 g, 5.182 mmol) and the mixture stirred at rt for 5 min.4-(Chloromethyl)-1-(2,4-difluorophenyl)-1H-pyrazole (Step 1, 0.74 g,3.109 mmol) was added to the mixture drop wise at 0° C. and themixture-stirred at 60° C. for 4 hr. The reaction was evaporated todryness in vacuo and diluted with EtOAc (150 mL), washed with brine(2×100 mL) and dried (Na₂SO₄). The organics were evaporated to drynessin vacuo to give a residue which was purified by column chromatographyon silica gel eluting with MeOH in DCM (0%-5%) to afford the titlecompound as a yellow solid (750 mg, 54%). ¹HNMR (400 MHz, DMSO-d₆): 2.94(s, 3H), 3.17 (s, 3H), 5.43 (s, 2H), 7.24 (t, 1H), 7.52 (t, 1H), 7.76(t, 1H), 7.80 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 8.50 (s, 1H), 8.87(s, 1H), 9.49 (s, 2H). LCMS m/z=528.1 [MH]⁺

Preparation 2:N′-(7-{1-[1-(4-Fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution of 1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethanol (869 mg,4.2 mmol) in DCM (20 mL) was added SOCl₂ (613 μL) at 0° C. and thesolution stirred at 40° C. for 2 hrs. The reaction mixture wasevaporated to dryness,N,N-dimethyl-N′-[5-(2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 1.4 g, 4.2 mmol), CS₂CO₃ (5.46 g, 16.8 mmol) and DMF(30 mL) added and the reaction stirred at 80° C. for 14 hr. The cooledmixture was poured into water (15 mL) and extracted with EtOAc (15mL×3). The combined organic layers were washed by brine (20 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography on silica gel to provide the title compound as anoff-white solid, (800 mg, 36%). LCMS m/z=524.1 [MH]⁺

Preparation 3:N′-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution of 4-(1-chloroethyl)-1-(2,4-difluorophenyl)-1H-pyrazole(Preparation 146, 1.08 g, 4.45 mmol) in DMF (30 mL) was added(E)-N-methyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 0.99 g, 52.97 mmol) and CS₂CO₃ (4.84 g, 14.85 mmol) andthe mixture stirred at 90° C. for 6 hr under N₂. The reaction mixturewas diluted with water and extracted (EtOAc). The combined extracts werewashed (brine), dried (Na₂SO₄) and evaporated to dryness in vacuo. Theresidue was purified by prep-HPLC to give the title compound (400 mg,25%). LCMS m/z=542.1 [MH]⁺

Preparation 4:N′-(7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution of 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole(preparation 100, 0.58 g, 2.42 mmol) in DMF (30 mL) was addedN,N-dimethyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 0.54 g, 1.61 mmol) and CS₂CO₃ (2.62 g, 8.05 mmol) andthe reaction stirred at 90° C. under N₂ overnight. The reaction wasquenched with H₂O, extracted with EtOAc (100 mL×2) and the combinedorganics washed with brine, dried and evaporated to dryness in vacuo.The residue was purified by column chromatography over silica gel(DCM:MeOH=9:1) to give the title compound (0.3 g, 35%). ¹HNMR (400 MHz,DMSO-d₆): 0.80 (t, 3H), 2.31 (m, 2H), 2.95 (s, 3H), 3.17 (s, 3H), 5.97(t, 1H), 7.30-7.50 (m, 3H), 7.74 (t, 1H), 7.90 (s, 1H), 8.21 (s, 1H),8.31 (s, 1H), 8.47 (s, 1H), 8.87 (s, 1H), 9.52 (s, 2H). LCMS m/z=538.1[MH]⁺

Preparation 5:N′-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

Step 1: SOCl₂ (976 mg, 8.4 mmol) was added drop wise to a solution of1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-ol (Preparation 104,1.0 g, 4.2 mmol) in DCM (40 mL) at 0° C. The reaction was stirred at rtfor 3 hrs and evaporated to dryness to afford4-(1-chloropropyl)-1-(2,4-difluorophenyl)-1H-pyrazole (1.1 g, crude) asa brown oil, which was used directly in next step without furtherpurification. LCMS m/z=253.2 [MH]⁺

Step 2: To a mixture ofN,N-dimethyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 1.44 g, 4.28 mmol) in DMF (30 mL) was added Cs₂CO₃(6.95 g, 21.4 mmol) and4-(1-chloropropyl)-1-(2,4-difluorophenyl)-1H-pyrazole (1.1 g, 4.28 mmol)and the mixture was stirred at 80° C. for 16 h. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween water (50 mL) and EtOAc (30 mL). The layers were separated andthe aqueous phase extracted with additional EtOAc (30 mL×3). Thecombined organic extracts were dried (Na₂SO₄) and evaporated to drynessunder reduced pressure. The residue was purified by silica gelchromatography eluting with methanol in dichloromethane from 0 to 10% in20 minutes to give the title compound as a brown solid (650 mg, 27% for2 steps). ¹HNMR (400 MHz, DMSO-d₆): 0.83 (t, 3H), 2.33 (q, 2H), 2.95 (s,3H), 3.17 (s, 3H), 5.96 (q, 1H), 7.22 (t, 1H), 7.52 (m, 1H), 7.75 (m,1H), 7.80 (s, 1H), 8.20 (s, 1H), 8.28 (s, 1H), 8.46 (s, 1H), 8.87 (s,1H), 9.52 (s, 2H). LCMS m/z=556.2 [MH]⁺

Preparation 6:N′-{5-(4-Methoxypyrimidin-5-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-N,N-dimethylformimidamide

To a stirred solution ofN′-[5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidoformamide (Preparation 19, 1 g, 3.36mmol) and 4-(1-chloropropyl)-1-phenyl-1H-1,2,3-triazole (Preparation119, 895 mg, 4.06 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.74 g, 8.41mmol) and the reaction stirred at 60° C. for 5 hr. The cooled reactionmixture was diluted with EtOAc and washed with water followed by brine.The organic phase was dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with MeOH:DCM (3:97) to afford the title compound as an offwhite solid (1 g, 61.7%). ¹HNMR (400 MHz, DMSO-d₆): 0.85 (t, 3H), 2.38(m, 2H), 2.75 (s, 3H), 3.10 (s, 3H), 3.87 (s, 3H), 6.11 (m, 1H), 7.48(m, 1H), 7.59 (m, 2H), 7.71 (s, 1H), 7.88 (d, 1H), 8.41 (s, 1H), 8.67 (s1H), 8.72 (d, 2H), 8.95 (s, 1H). LCMS m/z=482.8 [MH]⁺

Preparation 7:N′-(7-(1-(2-(2,4-difluorophenyl)-2H-imidazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

Step 1: SOCl₂ (5 mL) was added drop wise to a solution of1-(2-(2,4-difluorophenyl)-1H-imidazol-4-yl)propan-1-ol (Preparation 137,1.4 g, 5.88 mmol) in DCM (50 mL). The reaction was stirred at rt for 2hrs and evaporated to dryness in vacuo to give4-(1-chloropropyl)-2-(2,4-difluorophenyl)-1H-imidazole which useddirectly in Step 2 (1.4 g, 92%).

Step 2: To a solution ofN,N-dimethyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 1.22 g, 3.64 mmol) in DMF (50 mL) was added4-(1-chloropropyl)-2-(2,4-difluorophenyl)-1H-imidazole (Step 1, 1.4 g,5.45 mmol) and Cs₂CO₃ (5.93 g, 18.2 mmol). The reaction was stirred at90° C. overnight, cooled and extracted with EtOAc. The organic layer waswashed with brine, dried and evaporated. The residue was purified bycolumn chromatography over silica gel (DCM:MeOH=9:1) to afford the titlecompound (450 mg, 22%). LCMS m/z=556.1 [MH]⁺

Preparation 8:N′-(7-(1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution ofN,N-dimethyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide(Preparation 17, 839 mg, 2.5 mmol) in DMF (30 mL) was added Cs₂CO₃ (3.25g, 10 mmol) and4-(1-chloroethyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole(Preparation 114, 600 mg, 2.5 mmol). The mixture was stirred at 80° C.for 16 hr and the cooled reaction mixture then poured into water (20 mL)and extracted with EtOAc (15 mL×3). The combined extracts were washedwith brine (10 mL), dried (Na₂SO₄) and evaporated to dryness in vacuo.The residue triturated with pet. ether to afford the title compound as abrown solid (900 mg, 66%). LCMS m/z=539.1 [MH⁺]

Preparation 9:N′-(7-(1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution of4-(1-chloropropyl)-1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole(Preparation 111, 2.2 g, 8.83 mmol) in DMF (80 mL) was addedN,N-dimethyl-N′-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide (Preparation 17, 2.96 g, 8.83 mmol) and Cs₂CO₃ (11.5 g,35.32 mmol). The reaction mixture was stirred at 80° C. for 5 hr, pouredinto water (100 mL) and extracted with EtOAc (50 mL×3). The organicextracts were washed (brine, 100 mL), dried (Na₂SO₄) and evaporated todryness in vacuo. The residue was purified by combi-flash eluting withEtOAc in pet. ether (20-80%) to give the title compound as an off-whitesolid (2.8 g, 55%). ¹HNMR (400 MHz, MeOD-d₄): 0.87 (t, 3H), 2.44 (m,2H), 2.76 (s, 3H), 2.89 (s, 6H), 6.04 (t, 1H), 7.11 (m, 1H), 7.24 (m,1H), 7.52 (m, 1H), 7.88 (s, 1H), 8.34 (s, 1H), 8.58 (s, 1H), 9.29 (s,2H). LCMS m/z=571 [MH]⁺

Preparation 10:N′-(7-((1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution ofN′-(5-(6-methoxypyridin-3-yl)-6-methyl-7-(prop-2-ynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 11, 0.23 g, 0.66 mmol) in toluene (20 mL) was added underN₂ t-BuOH (5 mL), DIPEA (2 mL), 1-azido-2,4-difluorobenzene (0.26 g,1.65 mmol) and CuI (76 mg, 0.40 mmol). The reaction was stirred at rtovernight, water added and the mixture was extracted with EtOAc. Theorganic layer was collected, washed with brine, dried and evaporated todryness in vacuo. The residue was purified by column chromatography oversilica gel (DCM/MeOH=9/1) to afford the title compound as a solid, (0.22g, 66.2%). ¹HNMR (400 MHz, DMSO-d₆): 2.50 (s, 3H), 2.79 (s, 3H), 3.06(s, 3H), 3.87 (s, 3H), 5.67 (s, 2H), 6.83 (d, 1H), 7.33 (m, 1H), 7.65(m, 1H), 7.75-7.90 (m, 2H), 8.19 (s, 1H), 8.61 (s, 1H), 8.68 (s, 2H).

Preparation 11:N′-(5-(6-methoxypyridin-3-yl)-6-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution ofN′-(5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 12, 0.42 g, 1.35 mmol) in DMF (25 mL) was added NaH (60%,81 mg, 2.03 mmol) portion wise and stirred for 10 mins.3-Bromoprop-1-yne (0.24 g, 2.03 mmol) was added and the reaction stirredat rt overnight. The reaction was carefully quenched with water andextracted with EtOAc. The combined organics were washed with brine,dried and evaporated to dryness in vacuo. The residue was purified bycolumn chromatography over silica gel (EtOAc/MeOH=10/1) to afford thetitle compound (0.23 g, 48.9%) as a grey solid.

LCMS m/z=349.2 [MH]⁺

Preparation 12:N′-(5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

A solution of5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 23, 0.45 g, 1.7 mmol) in DMF-DMA (30 mL) was stirred at100° C. for 2 hrs. The mixture was evaporated to dryness in vacuo andthe residue diluted with EtOAc and NaHCO₃ solution. The organic layerwas washed with brine, dried and evaporated to dryness to give the titlecompound (0.42 g, 79.6%) as a solid. LCMS m/z=311.2 [MH]⁺; RT [HPLCmethod A]=1.183 min.

Preparation 13:N′-[7-(But-3-yn-2-yl)-5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidoformamide

Sodium ethoxide (66.4 mg, 0.96 mmol) was added to an ice cooled solutionofN′-[7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidoformamide(Preparation 14, 200 mg, 0.637 mmol) in anhydrous DMF (4 mL) and themixture stirred for 30 mins. 3-Bromo-1-butyne (0.134 mL, 1.27 mmol) wasadded drop wise and the reaction stirred at rt for 18 hrs. The mixturewas diluted with water and extracted with EtOAc, the combined organiclayers washed with brine, dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel eluting with EtOAc:heptane (20:80 to 100:0) to afford thetitle compound as an oil. LCMS m/z=366.1 [MH]⁺

Preparation 14:N′-(5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

A solution of5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 79, 300 mg, 1.16 mmol) in N,N-dimethylformamide dimethylacetal (4.8 mL) was stirred at rt for an hour, and then a further 16 hrsat 50° C. The cooled mixture was diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried(MgSO₄), filtered and evaporated under reduced pressure to afford thetitle compound as an off white solid (350 mg, 96.2%). LCMS m/z=314.1[MH]⁺

Preparation 15:N′-(7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a stirred solution ofN′-(5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 16, 50 mg, 0.16 mmol) in DMF (1.5 mL) was added NaH (9.56mg, 0.24 mmol) at 0° C. After 15 mins, 3-bromo-but-1-yne (0.022 mL, 0.24mmol) was added and the reaction stirred to rt for 16 hrs. The reactionmixture was diluted with EtOAc, washed with water, brine, dried (Na₂SO₄)and evaporated to dryness in vacuo. The residue was purified by prep-TLCusing 50% EtOAc:Hexane to afford the title compound as an off-whitesolid (30 mg, 51.5%). ¹HNMR (400 MHz, CDCl₃): 1.79 (d, 3H), 2.43 (s,3H), 2.77 (s, 3H), 3.00 (s, 3H), 6.14 (m, 2H), 7.32 (d, 2H), 7.39 (d,2H), 8.45 (s, 1H), 8.50 (brs, 1H).

Preparation 16:N′-(5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

N,N-dimethylformamidedimethylacetal (2.0 mL) was added to a5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 24, 100.0 mg, 0.4 mmol) at 0° C. and stirred at rt for 16hrs. The reaction mixture was evaporated to dryness and diluted withEtOAc, washed with water, brine, dried (Na₂SO₄) and evaporated in vacuoto afford the title compound as a light brown solid (80.0 mg, 66%). LCMSm/z=314.2 [MH]⁺

Preparation 17:N,N-dimethyl-N′-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formimidamide

A solution of5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 18, 24 g, 85.7 mmol) in DMF-DMA (300 mL) was heated to 100°C. for 3 hr. The cooled mixture was concentrated in vacuo and the crudeproduct purified by silica gel column chromatography eluting withDCM:MeOH=20:1 to afford the title compound (25 g, 87%) as a yellowsolid. ¹HNMR (400 MHz, DMSO-d₆): 2.96 (s, 3H), 3.16 (s, 3H), 7.92 (s,1H), 8.39 (s, 1H), 8.86 (s, 1H), 9.52 (s, 2H). LCMS m/z=336.1 [MH]⁺

Preparation 18:5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-[2-(trifluoromethyl)pyrimidin-5-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 25, 38 g, 92.7mmol) in DCM (200 mL) was slowly added TFA (100 mL) at 0° C. and thereaction stirred at rt for 16 hrs. The reaction mixture was concentratedand the pH adjusted to 8 using aqueous ammonia. The resulting mixturewas stirred for 16 hrs, the filtered to afford the title compound (24 g,92%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): 6.53 (s, 2H), 7.61 (s,1H), 8.18 (s, 1H), 9.06 (s, 2H). LCMS m/z=243.4, 245.2 [MH]⁺

Preparation 19:N′-[5-(4-Methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidoformamide

A stirred solution of5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 20, 3 g, 12.38 mmol) in DMF-DMA (45 mL) was heated at 60°C. for 12 hr. The cooled reaction mixture was concentrated in vacuo andthe product washed with hexane to afford the title compound as a greysolid (3 g, 81.5%). ¹HNMR (400 MHz, DMSO-d₆): 2.77 (s, 3H), 3.10 (s,3H), 3.90 (s, 3H), 7.48 (s, 1H), 8.30 (s, 1H), 8.66 (s, 1H), 8.73 (s,1H), 8.74 (s, 1H), 11.98 (s, 1H). LCMS m/z=298.1 [MH]⁺

Preparation 20:5-(4-Methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-(4-methoxypyrimidin-5-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 27, 32 g, 85.90 mmol) in DCM (300 mL) was added TFA (131.5mL, 1718.1 mmol) at 0° C. and the reaction stirred at rt for 16 hrs. Thereaction mixture was concentrated in vacuo, the residue diluted withMeOH and aqueous ammonia (150 mL) added. The resulting solution wasstirred at rt for 12 hrs and the reaction mixture then concentrated andfiltered. The resulting solid was washed with water, followed by 10%MeOH:DCM and dried under vacuum to afford the title compound as a graysolid (18.2 g, 87.5%). ¹HNMR (400 MHz, DMSO-d₆): 3.94 (s, 3H), 6.14(brs, 2H), 7.26 (s, 1H), 8.08 (s, 1H), 8.41 (s, 1H), 8.75 (s, 1H), 11.82(s, 1H). LCMS m/z=243.2 [MH]⁺

Preparation 21:N′-(5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

A solution of5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 22, 1 g, 4.145 mmol) in DMF-DMA (20 mL) was stirred at 60°C. for 6 h. The reaction mixture was evaporated under reduced pressureand the resulting solid was triturated with Et₂O to afford the titlecompound as a light brown solid (900 mg, 73%). ¹HNMR (400 MHz, DMSO-d₆):2.74 (s, 3H), 3.09 (s, 3H), 3.80 (s, 3H), 6.98 (dd, 1H), 7.39 (s, 1H),7.92 (d, 1H), 8.05 (d, 1H), 8.31 (s, 1H), 8.67 (s, 1H), 11.83 (s, 1H).LCMS m/z=297.4 [MH]⁺

Preparation 22:5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as a white solid (11 g, 84.5%) from5-(2-methoxypyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 26, 20 g, 53.77 mmol) following a similar procedure to thatdescribed in Preparation 190. ¹HNMR (400 MHz, DMSO-d₆): 3.87 (s, 3H),5.91 (brs, 2H), 7.07 (m, 1H), 7.20 (s, 1H), 7.63 (m, 1H), 8.08 (s, 1H),8.16 (m, 1H), 11.79 (s, 1H). LCMS m/z=242.0 [MH]⁺

Preparation 23:5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of5-(6-methoxypyridin-3-yl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 28, 0.8 g, 2.1mmol) in 25% TFA in DCM (30 mL) was stirred at rt overnight. The mixturewas concentrated and excess NaHCO₃ solution was added. The mixture wasextracted with DCM and the combined organics washed with brine, driedand evaporated to dryness. The residue was washed with TBME to give thetitle compound (0.45 g, 83.9%) as a grey solid. LCMS m/z=256.2 [MH]⁺

Preparation 24:5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

TFA (2.4 mL, 30.7 mmol) was added to a stirred solution of5-(4-chlorophenyl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 29, 400 mg, 1.023 mmol) in DCM (10.0 mL) at 0° C. andstirred at rt for 16 hrs. The reaction mixture was evaporated to drynessunder reduced pressure and the residue dissolved in methanol (3 mL) andtreated with NH₄OH (6 mL) and the mixture was stirred at rt for 16 hrs.The reaction mixture was evaporated to dryness in vacuo to afford thetitle compound as a brown solid (200 mg, 75%). LCMS m/z=259.0 [MH]⁺

Preparation 25:5-[2-(trifluoromethyl)pyrimidin-5-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 33, 43 g, 110 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (36.2 g, 132 mmol) in 1,4-dioxane (220 mL) at rt was addedK₂CO₃ (30 g, 217 mmol) in H₂O (40 mL) and PdCl₂(dppf) (8.1 g, 11.1 mmol)under N₂ and the reaction stirred at 100° C. for 4 hrs. The cooledreaction was filtered and the filtrate concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel eluting with pet. ether:EtOAc (50:50) to afford the titlecompound (38 g, 84%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): 0.00(s, 9H), 0.93 (t, 2H), 3.64 (t, 2H), 5.64 (s, 2H), 6.73 (brs, 2H), 7.88(s, 1H), 8.31 (s, 1H), 9.13 (s, 2H). LCMS m/z=411.1 [MH]⁺

Preparation 26:5-(2-methoxypyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 33, 25 g, 64.05 mmol) in EtOH: water (4:1, 750 mL) wasadded 2-methoxypridin-3-yl boronic acid (14.69 g, 96.08 mmol) followedby Na₂CO₃ (27.15 g, 256.21 mmol) and the mixture degassed with Ar for 15min. Pd(PPh₃)₄ (7.39 g, 6.4 mmol) was added and the reaction was heatedat 100° C. for 3 hrs. The cooled mixture was diluted with water and thesolution extracted with EtOAc. The combined organic extracts were dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by column chromatography on silica gel to afford the titlecompound (40 g, 79% for composite batch) as a white solid. ¹HNMR (400MHz, DMSO-d₆): −0.08 (s, 9H), 0.84 (t, 2H), 3.56 (t, 2H), 3.87 (s, 3H),5.52 (s, 2H), 6.06 (brs, 2H), 7.10 (m, 1H), 7.39 (s, 1H), 7.55-7.64 (m,2H), 8.15 (s, 1H). LCMS m/z=372.4 [MH]⁺

Preparation 27:5-(4-Methoxypyrimidin-5-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 33, 35 g, 89.68 mmol) in EtOH: water (1.4 L, 4:1) was added4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(25.4 g, 107.61 mmol) followed by Na₂CO₃ (28.51 g, 269.0 mmol) and thereaction mixture was degassed with Ar for 15 mins. Pd(PPh₃)₄ (10.36 g,8.97 mmol) was added and the reaction stirred at 100° C. for 5 hrs. Thecooled mixture was diluted with water and extracted with DCM. Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography on silica geleluting with acetone-DCM (30:70) to afford the title compound as an offwhite solid (17.81 g, 53.4%). ¹HNMR (400 MHz, DMSO-d₆): 0.07 (s, 9H),0.84 (t, 2H), 3.58 (t, 2H), 3.94 (s, 3H), 5.52 (s, 2H), 6.34 (brs, 2H),7.46 (s, 1H), 8.15 (s, 1H), 8.40 (s, 1H), 8.77 (s, 1H). LCMS m/z=373.0[MH]⁺

Preparation 28:5-(6-methoxypyridin-3-yl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 34, 1.5 g, 3.7 mmol) in dioxane (60 mL) was added6-methoxypyridin-3-ylboronic acid (0.85 g, 5.6 mmol), NaHCO₃ solution(15 mL) and Pd(PPh₃)₄ (0.21 g, 0.185 mmol) and the reaction stirred at100° C. overnight under N₂. The cooled reaction mixture was diluted withwater and extracted with EtOAc. The combined organics were washed withbrine, dried and evaporated to dryness. The residue was purified bycolumn chromatography over silica gel (pet. ether:EtOAc=3:1) to give thetitle compound as a yellow solid (0.8 g, 56.1%). ¹HNMR (400 MHz, CDCl₃):0.00 (s, 9H), 0.98 (t, 2H), 2.42 (s, 3H), 3.64 (t, 2H), 4.05 (s, 3H),5.68 (s, 2H), 6.92 (d, 1H), 7.45-7.75 (m, 3H), 8.26 (s, 1H), 8.33 (s,1H). LCMS m/z=256.2 [MH]⁺

Preparation 29:5-(4-chlorophenyl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a degassed solution of5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 34, 800 mg, 1.97 mmol), 4-chloro phenyl boronic acid (433.2mg, 2.77 mmol) and Na₂CO₃ (838.8 mg, 7.92 mmol) in EtOH-water (4:1, 20mL) under N₂ was added Pd(PPh₃)₄ (71.5 mg, 0.062 mmol) and the reactiondegassed with Ar for 15 min. The reaction was heated at 90° C. for 5hrs, filtered through a plug of Celite® and washed with EtOAc (2×30 mL).The combined filtrates were washed with water, dried (Na₂SO₄), andevaporated to dryness in vacuo. The residue was purified by columnchromatography on silica gel (20-25% EtOAc in hexane) to afford thetitle compound as a light yellow solid (400 mg, 51.98%). ¹HNMR (400 MHz,DMSO-d₆): −0.09 (s, 9H), 0.84 (t, 2H), 2.31 (s, 3H), 3.52 (t, 2H), 5.58(s, 2H), 5.80 (brs, 2H), 7.36 (d, 2H), 7.54 (d, 2H), 8.13 (s, 1H). LCMSm/z=389.0 [MH]⁺

Preparation 30:N′-(7-((5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

To a stirred solution of N′-(5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 21, 100 mg, 0.337mmol) in DMF was added Cs₂CO₃ (220.02 mg, 0.675 mmol) followed by3-(chloromethyl)-5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole(Preparation 121, 172.6 mg, 0.506 mmol, as mixture of isomers) and themixture stirred at rt for 16 hr. The reaction was diluted with ice waterand extracted with EtOAc (30 mL×2). The combined extracts were washedwith water, brine, dried (Na₂SO₄) and evaporated to dryness in vacuo.The residue was purified by column chromatography on silica gel toafford the title compound as a sticky yellow solid (160 mg, 78%, mixtureof two isomers). The mixture of isomers was used without furtherpurification. LCMS m/z=602 [MH]⁺

Preparation 31:N′-(5-(2-methoxypyridin-3-yl)-7-((5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

The title compound was prepared (140 mg, 71%) as a mixture of isomers inan analogous way to Preparation 30 using3-(chloromethyl)-5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole(Preparation 122, 163.5 mg, 0.506 mmol) andN′-(5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 21, 100 mg, 0.337 mmol). ¹HNMR (400 MHz, DMSO-d₆): −0.09(s, 6H), 0.79 (t, 2H), 3.08 (s, 3H), 3.57 (t, 2H), 3.80 (s, 3H), 5.75(s, 2H), 6.98 (m, 1H), 7.41-7.46 (m, 3H), 7.60 (s, 1H), 7.95 (m, 3H),8.05 (m, 1H), 8.37 (s, 1H), 8.71 (s, 1H). LCMS m/z=584.2 [MH]⁺

Preparation 32:N′-(7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

A mixture of7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 57, 160 mg, 0.352 mmol) in DMF-DMA (8 mL) was stirred at 90° C.for 0.5 hr. The mixture was concentrated to give the crude product whichwas purified by combi-flash on a silica column eluting with MeOH in DCM(0%-5%) to give the title compound as an orange solid (110 mg, 61%).¹HNMR (400 MHz, DMSO-d₆): −0.09 (s, 9H), 0.84 (t, 2H), 2.31 (s, 3H),3.52 (t, 2H), 5.58 (s, 2H), 5.80 (brs, 2H), 7.36 (d, 2H), 7.54 (d, 2H),8.13 (s, 1H). LCMS m/z=510.1 [MH]⁺

Preparation 33:5-Iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-amine

To a stirred solution of4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine(Preparation 72, 40 g, 97.8 mmol) in dioxane: MeOH (110 mL, 5:1) wasadded NH₄OH_((aq)) (570 mL) and the resulting suspension stirred in anautoclave at 70° C. for 2 hr then at 90° C. for 16 hr. The cooledreaction mixture was diluted with DCM, the layers separated and theorganic layer washed with brine, dried (Na₂SO₄) and concentrated invacuo. The crude product was triturated with diethyl ether and driedunder reduced pressure to afford the title compound as an off-whitesolid (32 g, 83.84%). ¹HNMR (400 MHz, DMSO-d₆): 0.09 (s, 9H), 0.82 (t,2H), 3.48 (t, 2H), 5.44 (s, 2H), 6.66 (brs, 2H), 7.56 (s, 1H), 8.12 (s,1H). LCMS m/z=391.0 [MH]⁺

Preparation 34:5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

NH₄OH was added to a stirred solution of4-chloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 73, 1 g, 2.36 mmol) in dioxane (25.0 mL) (75 mL) and heatedto 120° C. for 16 hrs. The reaction was evaporated to dryness in vacuoand extracted with EtOAc (3×25 mL), washed with water, brine, dried(Na₂SO₄) and evaporated to dryness. The residue was purified by columnchromatography to afford the title compound as an off white solid (400mg, 42.11%). ¹HNMR (400 MHz, DMSO-d₆): −0.10 (s, 9H), 0.82 (t, 2H), 2.38(s, 3H), 3.45 (t, 2H), 5.54 (s, 2H), 6.58 (brs, 2H), 8.09 (s, 1H). LCMSm/z=405.2 [MH]⁺

Preparation 35:4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

(4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronicacid (Preparation 61, 340 mg, 0.88 mmol), powdered Nil (40 mg, 0.12mmol) and trans-2-aminocyclohexanol (20 mg, 0.12 mmol) were suspended inanhydrous iPrOH (1.25 mL) and DMSO (1.75 mL). NaHMDS (1M in THF, 0.97mL, 0.97 mmol) was added, the suspension degassed under N₂, iodo-oxetane(70 μL, 0.79 mmol) in anhydrous iPrOH (0.5 mL) added and the reactionheated at 80° C. for 30 mins under microwave irradiation. The mixturewas partitioned between water and EtOAc, the layers separated, theaqueous extracted with EtOAC and the combined organics dried (MgSO₄),filtered, and concentrated in vacuo. The crude yellow oil was purifiedby column chromatography on silica gel eluting with EtOAc:heptane (50:50to 100:0) to afford the title compound as a yellow oil (77.4 mg, 14)%.¹HNMR (400 MHz, DMSO-d₆): 1.98 (d, 3H), 4.50-4.60 (m, 3H), 5.04 (m, 2H),6.38 (q, 1H), 7.45 (m, 1H), 7.54-7.62 (m, 2H), 7.73 (m, 1H), 8.17 (s,1H), 8.70 (s, 2H). LCMS m/z=399.0 [MH]⁺

Preparation 36:4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine

A suspension of(4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronicacid (Preparation 61, 35 mg, 0.074 mmol),5-bromo-4-methoxy-2-(trifluoromethyl)pyrimidine (Preparation 141, 19 mg,0.074 mmol) and Na₂CO₃ (32 mg, 0.3 mmol) in EtOH (4.5 mL) and H₂O (0.5mL) was degassed with N₂. Pd(PPh₃)₄ (8 mg) was added and the reactionstirred at 90° C. for 2 hrs. The solvents were blown off under a streamof N₂, the residue partitioned between water and EtOAc, the layersseparated and the aqueous extracted with EtOAc. The combined organicextracts were dried (MgSO₄) filtered, and concentrated in vacuo toafford the title compound in quantitative yield. The product was usedwithout further purification. LCMS m/z=519.0 [MH]⁺

Preparation 37:4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

A suspension of4-chloro-7-(1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 63, 827 mg, 1.71 mmol), 2-chloro-3-methoxypyrazine (521 mg,3.61 mmol), and Na₂CO₃ (726 mg, 6.85 mmol) in EtOH (9 mL) and H₂O (1.5mL) was degassed under N₂. Pd(PPh₃)₄ (198 mg, 0.17 mmol) was added andthe reaction stirred at 90° C. The cooled reaction was partitionedbetween, water and EtOAc, the layers separated and the aqueous phaseextracted with EtOAc. The combined organic layers were dried (MgSO₄),filtered, and concentrated to give a yellow oil. This was purified bycolumn chromatography on silica gel eluting with EtOAc:DCM (40:60 to100:0) to afford the title compound as an off-white foam (370 mg,46.6%). ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.48 (m, 2H), 3.90 (s,3H), 6.25 (m, 1H), 7.45 (m, 1H), 7.52-7.62 (m, 2H), 7.84 (m, 1H),8.22-8.30 (m, 3H), 8.78 (s, 1H), 8.82 (d, 1H). LCMS m/z=465.1 [MH]⁺

Preparation 38:5-(4-Chlorophenyl)-7-(1H-pyrazol-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of 5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 80, 5.43 g, 22.2 mmol) in DMF (120 mL) was added CS₂CO₃(14.5 g, 44.4 mmol) and 4-(chloromethyl)-1H-pyrazole hydrochloride (5.1g, 33.3 mmol) and the reaction heated at 60° C. for 12 hrs. The cooledmixture was diluted with water, extracted with EtOAc, the organic phasewashed with brine and dried (Na₂SO₄). The residue was purified by columnchromatography on silica gel eluting with DCM:MeOH (15:1) to afford thetitle compound as a white solid (1.1 g, 15% yield). ¹HNMR (400 MHz,DMSO-d₆): 5.24 (s, 2H), 6.17 (br s, 2H), 7.40-7.76 (m, 7H), 8.19 (s,1H), 12.81 (s, 1H). LCMS m/z=325.2 [MH]⁺

Preparation 39:5-(2-methoxypyridin-3-yl)-7-(1H-pyrazol-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-(2-methoxypyridin-3-yl)-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 40, 22 g, 48.78 mmol) in DCM (300 mL) was added TFA (37.35mL, 487.8 mmol) at 0° C. and the reaction stirred at rt for 16 hr. Thereaction mixture was concentrated and diluted with cold water. Aqueousammonia was added and the solution stirred at rt for 24 hr. Theresulting mixture was filtered, the solid washed with water, thendiethyl ether and dried under vacuum. The solid was suspended inDCM/MeOH and purified by passing through a neutral alumina bed to affordthe title compound as a white sold (10 g, 67.7%). ¹HNMR (400 MHz,DMSO-d₆): 3.85 (s, 3H), 5.21 (s, 2H), 5.98 (brs, 2H), 7.06 (m, 1H), 7.32(s, 1H), 7.43-7.77 (m, 3H), 8.16 (s, 2H), 12.76 (s, 1H). LCMS m/z=323[MH]⁺

Preparation 40:5-(2-methoxypyridin-3-yl)-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 74, 35 g, 74.4 mmol) in EtOH: water (4:1, 875 mL) was added2-methoxypyridin-3-yl boronic acid (17.07 g, 111.61 mmol) followed byNa₂CO₃ (31.54 g, 297.62 mmol) and the mixture degassed with Ar for 15mins. Pd(PPh₃)₄ (8.59 g, 7.44 mmol) was added and the reaction washeated at 100° C. for 3 hrs. The cooled reaction mixture was dilutedwith water, the solution extracted with EtOAc, the combined organicextracts dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel toafford the title compound (22 g, 65.5%) as an off white solid. ¹HNMR(400 MHz, DMSO-d₆): −0.12 (s, 9H), 0.78 (t, 2H), 3.47 (t, 2H), 3.85 (s,3H), 5.23 (s, 2H), 5.33 (s, 2H), 6.00 (brs, 2H), 7.06 (m, 1H), 7.32 (s,1H), 7.56 (s, 1H), 7.61 (m, 1H), 7.89 (s, 1H), 8.16 (s, 2H). LCMSm/z=452.0 [MH]⁺

Preparation 41:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 85, 60 g, 0.201 mol), CuI (21.08 g, 0.11 mol), DIPEA (347.4mL, 2.01 mol) and 1-azido-2-fluorobenzene (56.92 g, 0.362 mol) intoluene (1.9 L) and t-BuOH (480 mL) was stirred at rt for 16 hr. Thereaction was diluted with hexane (500 mL) and the mixture filtered underreduced pressure. The resulting solid was suspended in saturatedmethanolic NH₃: DCM (1:5, 2 L) and filtered through Celite® washingthrough with saturated methanolic NH₃: DCM (1:5, 5×500 mL). The filtratewas concentrated under reduced pressure the residue triturated withdiethyl ether (200 mL), filtered and dried to afford the title compoundas a light yellow solid (40 g, 45.9%). ¹HNMR (400 MHz, DMSO-d₆): 5.50(s, 2H), 6.64 (br s, 2H), 7.41 (m, 1H), 7.53-7.63 (m, 3H), 7.79 (m, 1H),8.14 (s, 1H), 8.57 (s, 1H). LCMS m/z=436.0 [MH]⁺

Preparation 42:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation86, 19 g, 60.88 mmol) in toluene (37.5 mL) was added t-BuOH (12.5 mL),CuI (5.80 g, 30.44 mmol) and DIPEA (99.75 mL, 547.88 mmol) at rt. Themixture was cooled to 0° C. 1-azido-2-fluoro-benzene (14.39 g, 103.49mmol) added and the reaction stirred for 16 hrs at rt. The mixture wasfiltered, the resulting solid suspended in hot THF and the mixturefiltered to afforded the crude material. This material was washed withEt₂O and dried in vacuo to afford the title compound as a brown solid(22.2 g, 81.17%). ¹HNMR (400 MHz, DMSO-d₆): 1.87 (d, 3H), 6.21-6.26 (m,1H), 6.62-6.76 (brs, 2H), 7.43 (m, 1H), 7.54-7.63 (m, 3H), 7.80-7.84 (m,1H), 8.17-8.29 (m, 1H), 8.64 (s, 1H). LCMS m/z=450.0 [MH]⁺

Preparation 43:7-{1-[1-(3-Fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation86, 700 mg, 2.24 mmol) in a mixture of toluene:tBuOH (3:1) (70 mL) wasadded 2-azido-3-fluoropyridine (Preparation 144, 624.16 mg, 4.49 mmol),DIPEA (4.02 mL, 22.44 mmol) and CuI (235 mg, 1.23 mmol) successively at0° C. under N₂ and the reaction stirred at rt for 24 hrs. The mixturewas diluted with EtOAc and washed with water followed by brine. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel eluting withMeOH:DCM (4:96) to afford the title compound as an off-white solid (250mg, 24.75%). ¹HNMR (400 MHz, DMSO-d₆): 1.88 (d, 3H), 6.22-6.27 (m, 1H),6.63 (brs, 2H), 7.60 (s, 1H), 7.69-7.73 (m, 1H), 8.13-8.17 (m, 2H), 8.48(m, 1H), 8.72 (s, 1H). LCMS m/z=450.8 [MH]⁺

Preparation 44:7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as a white solid (2.7 g, 72%) from7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation86) and 1-azido-2,4-difluorobenzene following an analogous procedure tothat described in preparation 43. ¹HNMR (400 MHz, DMSO-d₆): 1.89 (d,3H), 6.24 (m, 1H), 6.70-6.90 (brs, 2H), 7.33 (m, 1H), 7.59 (s, 1H), 7.68(m, 1H), 7.88 (m, 1H), 8.40 (s, 1H), 8.64 (s, 1H). LCMS m/z=468.0 [MH]⁺

Preparation 45:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

DIPEA (15 mL, 82.8 mmol) and CuI (876 mg, 4.6 mmol) were added to asolution of 5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 87, 3 g, 9.2 mmol) in toluene:t-BuOH (100 mL, 4:1) at 0°C., followed by 1-azido-2-fluorobenzene (2.2 g, 16.06 mmol) and thereaction stirred at rt or 16 hrs. The mixture was filtered, washingthrough with ether: hexane (1:4) and the filtrate evaporated underreduced pressure to afford the title compound as a light brown solid (3g, 96.15%). ¹HNMR (400 MHz, DMSO-d₆): 0.80 (t, 3H), 2.32 (m, 2H), 6.04(m, 1H), 6.64 (brs, 2H), 7.44 (m, 1H), 7.55-7.67 (m, 4H), 7.85 (m, 1H),8.15 (s, 1H), 8.48 (s, 1H). LCMS m/z=463.9 [MH]⁺

Preparation 46:7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 87, 70 g, 214.85 mmol) in toluene (200 ml) was added1-azido-2,4-difluorobenzene (50 g, 322.25 mmol), CuI (24.55 g, 128.9mmol), DIPEA (177.5 ml, 1.07 mol) and t-BuOH (750 ml) added under N₂ andthe reaction stirred at rt for 16 hrs. The mixture was filtered,concentrated in vacuo and the residue purified by flash chromatography(eluting with DCM:MeOH=20:1) to afford the title compound as a whitesolid (70 g, 67.8%). ¹HNMR (400 MHz, DMSO-d₆): 0.79 (t, 3H), 2.31 (m,2H), 6.00 (m, 1H), 6.65 (brs, 2H), 7.35 (m, 1H), 7.61 (s, 1H), 7.69 (m,1H), 7.90 (m, 1H), 8.14 (s, 1H), 8.67 (d, 1H). LCMS m/z=482.0 [MH]⁺

Preparations 47 to 53

The following compounds were prepared from5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 87) and the appropriate commercial azide, following theprocedure described in Preparation 46.

Preparation No Structure/Name Analytical Data 47

¹HNMR (400 MHz, DMSO-d₆): 0.78 (t, 3H), 2.25-2.33 (m, 2H), 5.98 (m, 1H),6.64 (br s, 2H), 7.42-7.58 (m, 3H), 7.97 (m, 2H), 8.17 (s, 1H), 8.88 (s,1H). LCMS m/z = 463.9 [MH]⁺ 48

¹HNMR (400 MHz, DMSO-d₆): 0.79 (t, 3H), 2.31 (m, 2H), 5.97 (m, 1H), 6.65(br s, 2H), 7.54 (s, 1H), 7.69 (m, 1H), 7.79 (m, 1H), 8.08-8.14 (m, 2H),8.90 (s, 1H). LCMS m/z = 482.0 [MH]⁺ 49

¹HNMR (400 MHz, DMSO-d₆): 0.79 (t, 3H), 2.31 (m, 2H), 6.01 (m, 1H), 6.66(br s, 2H), 7.50 (m, 1H), 7.63-7.68 (m, 2H), 7.84 (m, 1H), 8.14 (s, 1H),8.72 (s, 1H). LCMS m/z = 482.1 [MH]⁺ 50

¹HNMR (400 MHz, DMSO-d₆): 0.79 (t, 3H), 2.31 (m, 2H), 6.02 (m, 1H), 6.68(br s, 2H), 7.44 (m, 1H), 7.63-7.71 (m, 3H), 8.18 (s, 1H), 8.74 (s, 1H).LCMS m/z = 482.1 [MH]⁺ 51

LCMS m/z = 446.1 [MH]⁺ 52

¹HNMR (400 MHz, DMSO-d₆): 0.81 (t, 3H), 2.34 (m, 2H), 6.03 (m, 1H), 6.63(br s, 2H), 7.67 (s, 1H), 7.95 (d, 1H), 8.14 (s, 1H), 8.34 (s, 1H), 8.89(s, 1H), 9.03 (s, 1H). LCMS m/z = 514.8 [MH]⁺ 53

¹HNMR (400 MHz, DMSO-d₆): 0.38 (m, 1H), 0.53-0.60 (m, 2H), 0.71 (m, 1H),1.92 (m, 1H), 5.35 (d, 1H), 6.03 (m, 1H), 6.64 (br s, 2H), 7.45 (m, 1H),7.58-7.68 (m, 2H), 7.70 (s, 1H), 7.84 (m, 1H), 8.10 (s, 1H), 8.73 (s,1H). LCMS m/z = 475.8 [MH]⁺

Preparation 54:7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-iodo-2-methyl-7-prop-2-ynyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(Preparation 89, 3.8 g, 12.18 mmol) in toluene: t-BuOH (60 mL, 4:1) wasadded DIPEA (16.84 mL, 97.45 mmol), copper iodide (1.16 g, 6.09 mmol)and 1-azido-2-fluorobenzene (Preparation 145, 2.87 g, 20.71 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hr. Thereaction was evaporated to dryness in vacuo and water was added followedby ammonium hydroxide solution and the resulting mixture stirred for 30min and filtered (the process was repeated until the filtrate wascolorless). Solid was washed with 5% EtOAc in hexane and dried. Theresidue was purified by column chromatography (0.5% MeOH in DCM) toafford the title compound as an off-white solid (3.35 g, 61.4%). ¹HNMR(400 MHz, DMSO-d₆): 2.56 (s, 3H), 5.51 (s, 4H), 7.19 (s, 1H), 7.25-7.44(m, 3H), 7.93 (t, 1H), 8.08 (d, 1H). LCMS m/z=450.0 [MH]⁺

Preparation 55:7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of4-chloro-7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 67, 20 g, 44.2 mmol) and NH₄OH (100 mL) in 1,4-dioxane (50mL) was stirred at 100° C. in an autoclave for 8 hrs. The reactionmixture was cooled to rt, solids removed by filtration which were washedwith water to afford the title compound as a white solid (17 g, 89%).¹HNMR (400 MHz, DMSO-d₆): 5.27 (s, 2H), 6.63 (br s, 2H), 7.31-7.48 (m,3H), 7.56 (s, 1H), 7.74-7.79 (m, 2H), 8.16 (s, 1H), 8.25 (d, 1H). LCMSm/z=434.9 [MH]⁺

Preparation 56:7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In a sealed tube a solution of4-chloro-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 69, 0.5 g, 1.07 mmol) in dioxane (10 mL) and NH₃.H₂O (30mL) was stirred at 100° C. for 18 hrs. The reaction was diluted withEtOAc (100 mL) and organic layer collected, washed with brine, dried andevaporated in vacuo to give the title compound (360 mg, 75%). ¹HNMR (400MHz, DMSO-d₆): 1.81 (d, 3H), 6.04 (q, 1H), 6.50-6.75 (brs, 2H),7.30-7.48 (m, 3H), 7.60 (s, 1H), 7.75 (m, 2H), 8.18 (s, 1H), 8.22 (s,1H). LCMS m/z=449.1 [MH]⁺

Preparation 57:7-(1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The following reaction was carried out 4 times in parallel. To a stirredsolution of4-chloro-7-(1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 70, 2 g, 4.277 mmol) in 1,4-dioxane (35 mL) was added aq.NH₃ (75 mL) in a sealed tube and resulting suspension was heated to 130°C. for 16 hrs. The reaction was evaporated to dryness in vacuo and theresidue dissolved in H₂O and extracted with EtOAc. The combined organicswere washed with water, brine, dried (Na₂SO₄) and concentrated underreduced pressure to afford an impure sample of the title compound as abrown solid (2.02 g). The products of all four reactions were combinedand purified by flash chromatography to afford the title compound as anoff white solid (4.8 g, 62.6%). ¹HNMR (400 MHz, DMSO-d₆): 1.74 9d, 3H),5.98 (q, 1H), 6.59 (br s, 2H), 7.20-7.43 (m, 5H), 7.94 (t, 1H), 8.13 (s,1H), 12.19 (s, 1H). LCMS m/z=449 [MH]⁺

Preparation 58:7-((2-(2-fluorophenyl)-1H-imidazol-5-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

NH₄OH (75.0 mL) was added to a stirred solution of4-chloro-7-[2-(2-fluoro-phenyl)-3H-imidazol-4-ylmethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 68, 8 g, 17.63 mmol) in dioxane (25.0 mL) and the reactionheated for 16 hr at 120° C. The reaction mixture was evaporated todryness in vacuo and the residue extracted with EtOAc (3×100 mL). Thecombined organics were washed with water, then brine, dried (Na₂SO₄) andevaporated to dryness in vacuo. The residue was purified by columnchromatography on silica gel to afford the title compound as anoff-white solid (4 g, 52%). ¹HNMR (400 MHz, DMSO-d₆): 2.14 (s, 2H), 6.60(br s, 2H), 7.15 (s, 1H), 7.26-7.35 (m, 2H), 7.40 (m, 1H), 7.50 (s, 1H),7.94 (t, 1H), 8.14 (s, 1H). LCMS m/z=435 [MH]⁺

Preparation 59:7-(1-(3-(2-fluorophenyl)isoxazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation85, 15 g, 48.06 mmol) and 2-fluoro-N-hydroxybenzimidoyl chloride(Preparation 130, 12.51 g, 72.09 mmol) in toluene (600 mL) was addedEt₃N (11.32 mL, 81.70 mmol) at 0° C. The reaction was stirred at 60° C.for 16 hr. The solids were removed by filtration and the filtrate wasevaporated to dryness and the residue purified by column chromatographyon silica gel eluting with 50% EtOAc:hexane to afford the title compoundas an off white solid (11 g, 51%). ¹HNMR (400 MHz, DMSO-d₆): 1.90 (d,3H), 6.24 (q, 1H), 6.69 (brs, 2H), 6.89 (s, 1H), 7.33-7.42 (m, 2H), 7.55(m, 1H), 7.66 (s, 1H), 7.86 (t, 1H), 8.13 (s, 1H). LCMS m/z=450 [MH]⁺

Preparation 60:N′-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide

A solution of7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 41, 1.0 g, 2.99 mmol) in DMF-DMA (15 mL) was stirred at 80°C. overnight. The reaction mixture was evaporated to dryness in vacuo toafford the title compound (1.1 g, 98%) as a yellow solid. ¹HNMR (400MHz, DMSO-d₆): 3.20 (s, 3H), 3.25 (s, 3H), 5.58 (s, 2H), 7.43 (m, 1H),7.54-7.62 (m, 3H), 7.83 (m, 1H), 8.36 (s, 1H), 8.59 (s, 1H), 8.87 (s,1H). LCMS m/z=491 [MH]⁺

Preparation 61:(4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronicacid

Sodium periodate (2.24 g, 10.5 mmol) was added to4-chloro-7-{1-[1[(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 62, 2.46 g, 5.25 mmol) in THF (30 mL) and water (40 mL) andthe reaction stirred at rt for 18 hrs. The mixture was acidified to pH 2using 1N HCl, then poured into water and extracted with DCM (3×). Thecombined organics were dried (MgSO₄) filtered, and concentrated. Thecrude product was purified by column chromatography on silica geleluting with MeOH:EtOAc (0:100 to 5:95) to afford the title compound asan off-white foam (741 mg, 36.6%). ¹HNMR (400 MHz, DMSO-d₆): 1.98 (d,3H), 4.08 (brs, 1H), 6.38 (m, 1H), 6.73 (d, 1H), 7.43 (m, 1H), 7.54-7.65(m, 2H), 7.82 (m, 1H), 7.92 (s, 1H), 8.67 (s, 1H). LCMS m/z=386.9 [MH]⁺

Preparation 62: 4-Chloro-7-{1-[1[(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane solution in THF (9.2 mL, 1M, 9.2mmol) was added to a suspension of4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 65, 3.44 g, 7.3 mmol), Et₃N (1.3 mL, 9.2 mmol), Pd₂(dba)₃(400 mg, 0.37 mmol), and XPhos (361 mg, 0.73 mmol) in dioxane (37 mL)and the reaction stirred at 75° C. for 18 hrs. The cooled reaction wasdiluted with EtOAc, filtered through Celite® and the filtrate evaporatedunder reduced pressure. The crude dark orange oil was purified by columnchromatography on silica gel eluting with EtOAc:heptane (20:80 to 80:20)to afford the title compound as a yellow foam (2.46 g, 72%). ¹HNMR (400MHz, CDCl₃): 1.26 (s, 3H), 1.29 (s, 1H), 1.39 (2×s, 6H), 2.10 (d, 3H),6.43 (m, 1H), 7.26-7.37 (m, 2H), 7.45 (m, 1H), 7.92-8.01 (m, 3H), 8.76(s, 1H). LCMS m/z=469.1 [MH]⁺

Preparation 63:4-chloro-7-(1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was obtained (827 mg, 69%) from4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 66) following an analogous procedure to that described inpreparation 62. ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 1.32 (s, 12H),2.48 (m, 2H), 6.15 (m, 1H), 7.45 (m, 1H), 7.52-7.62 (m, 2H), 7.84 (m,1H), 8.15 (s, 1H), 8.70 (s, 1H), 8.82 (d, 1H). LCMS m/z=483.1 [MH]⁺

Preparation 64:4-Chloro-7-[1-(2-fluoro-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution4-chloro-7-[1-(2-fluoro-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 95, 2.5 g, 5.507 mmol) in degassed dioxane (50 mL) wasadded X-Phos (449 mg, 0.551 mmol), Pd₂(dba)₃ (226 mg, 0.275 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.03 mL, 22.03 mmol, 1M sol inTHF) and the mixture stirred at room temperature for 10 min. Et₃N (3.07mL, 22.026 mmol) was added and stirred at 75° C. for 2 hr. The reactionmixture was filtered through Celite® and evaporated to dryness in vacuo.The residue was purified by flash column chromatography (100% DCM) toafford the title compound as a pale yellow solid (2.2 g, 88%). ¹HNMR(400 MHz, CDCl₃): 1.35 (s, 12H), 5.65 (s, 2H), 7.25-7.32 (m, 2H), 7.42(m, 1H), 7.87-7.90 (m, 2H), 8.07 (d, 1H), 8.66 (s, 1H). LCMS m/z=455.0[MH]⁺

Preparation 65:4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

7-(But-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 91, 3.0 g, 9.0 mmol) was suspended in toluene (40 mL) andtBuOH (10 mL) under N₂, 1-azido-2-fluorobenzene (1.96 g, 13.6 mmol), CuI(0.95 mg, 5.0 mmol), and Hunig's base (16 mL, 90 mmol) added and thereaction stirred at rt for 18 hrs. The reaction was partitioned betweenEtOAc and water, the mixture filtered through Celite® and the layersseparated. The aqueous phase was extracted with EtOAc and the combinedorganic extracts were dried (MgSO₄), filtered, and concentrated invacuo. The light brown solid was triturated with Et₂O to remove residualazide. The crude product was purified by column chromatography on silicagel eluting with EtOAc:DCM (0:100 to 10:90) to afford the title compoundas a pale yellow solid (3.44 g, 81.7%). ¹HNMR (400 MHz, DMSO-d₆): 1.98(d, 3H), 6.35 (q, 1H), 7.45 (m, 1H), 7.54-7.61 (m, 2H), 7.84 (m, 1H),8.18 (s, 1H), 8.70 (m, 2H). LCMS m/z=469.1 [MH]⁺

Preparation 66:4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Step 1: 2-Fluorophenyl azide (2.26 g, 16.5 mmol), copper iodide (1.25 g,6.5 mmol), and Hunig's base (10 eq, 118 mmol, 21 mL) were added to asolution of 1-pentyn-3-ol (1 g, 12 mmol) in toluene (40 mL) and tBuOH(10 mL) under N₂. The suspension was stirred overnight at rt. Thereaction was concentrated in vacuo and partitioned between EtOAc and 15%NH₄OH. The aqueous layer was extracted with EtOAc (2×) and the combinedorganics vigorously shaken with 15% NH₄OH (2×) until the solution wasessentially colourless. The organics were dried (MgSO₄) and evaporatedto dryness in vacuo. The residue was purified using Biotage 50 g snapcartridge, eluting with 50-80-100% EtOAc/heptane gradient to afford1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propan-1-ol (2.29 g, 86.3%).¹HNMR (400 MHz, CDCl₃): 1.05 (t, 3H), 1.90-2.20 (m, 3H), 4.95 (m, 1H),7.30-7.50 (m, 2H), 8.00 (m, 2H), 8.10 (s, 1H). LCMS m/z=222.2 [MH]⁺

Step 2: 1-(1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)propan-1-ol (Step 1,1 g, 4.5 mmol) was dissolved in DCM (24 mL). SOCl₂ (5.0 mL, 67.8 mmol)was added slowly and the reaction stirred at rt for 2.5 hr. The reactionmixture was evaporated to dryness in vacuo and the resulting brown oilazeotroped a few times with toluene to remove the last traces of SOCl₂to afford 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-1,2,3-triazole (1.1g, 100%) which was used without further purification. LCMSm/z=242.1[MH]⁺

Step 3: 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 898mg, 3.21 mmol) was dissolved in DMF (20 mL), CS₂CO₃ (2.09 g, 6.43 mmol)added and the reaction stirred for 30 min at rt then cooled in anice/water bath. 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-1,2,3-triazole(Step 2, 1.54 g, 6.43 mmol) in DMF (7 mL) was added drop wise, thereaction allowed to warm to rt and then stirred at 50° C. for 24 hrs.The mixture was partitioned between water and EtOAc and the layersseparated. The organic layer was evaporated under reduced pressure andthe residual oil purified by column chromatography on silica gel elutingwith EtOAc: heptane (10:90 to 50:50) to afford the title compound (1.24g, 44%). ¹HNMR (400 MHz, CDCl₃): 0.95 (t, 3H), 2.42-2.60 (m, 2H), 6.15(m, 1H), 7.24-7.39 (m, 2H), 7.45 (m, 1H), 7.82 (s, 1H), 7.94 (m, 1H),8.10 (s, 1H), 8.64 (s, 1H). LCMS m/z=483.0 [MH]⁺

Preparation 67:4-chloro-7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation71, 20 g, 71.7 mmol) in DMF (200 mL) was added K2CO₃ (49.5 g, 358.5mmol) and the mixture stirred for 10 min at rt before4-(chloromethyl)-1-(2-fluorophenyl)-1H-pyrazole (Preparation 98, 20 g,95.2 mmol) was added. The resulting mixture was stirred at 60° C. for 6hr, filtered and concentrated under reduced pressure to give a crudeproduct which was washed with EtOAc and water to afford the titlecompound (20 g, 62.5%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃): 5.41(s, 2H), 7.20-7.32 (m, 3H), 7.42 (s, 1H), 7.72 (s, 1H), 7.84-7.87 (m,1H), 8.05 (d, 1H), 8.68 (s, 1H). LCMS m/z=453.9 [MH]⁺

Preparation 68:4-chloro-7-((2-(2-fluorophenyl)-1H-imidazol-5-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Cesium carbonate (42.43 g, 130.55 mmol) was added to a stirred solutionof 5-chloromethyl-2-(2-fluoro-phenyl)-1H-imidazole (Preparation 108, 11g, 52.22 mmol) in DMF (100 mL) at 0° C., followed by4-chloro-5-iodo-7H-pyrrolo[2,3-d] pyrimidine (Preparation 71, 14.6 g,52.22 mmol) in DMF (50 mL) at the same temperature. The reaction mixturewas stirred at rt for 16 hr, diluted with EtOAc. The combined organicswere washed with H₂O, brine and dried (Na₂SO₄) and evaporated to drynessin vacuo. The residue was purified by column chromatography on silicagel to afford the title compound as a yellow solid (8 g, 33.77%). ¹HNMR(400 MHz, MeOD-d₄): 5.48 (s, 2H), 7.20-7.26 (m, 3H), 7.41 (m, 1H), 7.79(s, 1H), 7.92 (t, 1H), 8.60 (s, 1H). LCMS m/z=453.8 [MH]⁺

Preparation 69:4-chloro-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 4-(1-chloroethyl)-1-(2-fluorophenyl)-1H-pyrazole(WO2013/071232 compound 32, 2.17 g, 9.7 mmol) in DMF (50 mL) was added4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 2.46 g, 8.8mmol) and Cs₂CO₃ (14.3 g, 44.0 mmol) and the reaction stirred at 60° C.for 18 hrs. After cooling, water was added and the mixture extractedwith EtOAc (60 mL×2). The organic extracts were collected, washed withbrine, dried and evaporated to give a residue which was purified bycolumn chromatography on silica gel (pet. ether/EtOAc=1/9) to afford thetitle compound (0.5 g, 12%). ¹HNMR (400 MHz, DMSO-d₆): 1.89 (d, 3H),6.20 (q, 1H), 7.30-7.50 (m, 3H), 7.72 (t, 1H), 7.76 (s, 1H), 8.16 (s,1H), 8.27 (s, 1H), 8.69 (s, 1H). LCMS m/z=468.0 [MH]⁺

Preparation 70:4-chloro-7-(1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 71, 5 g, 17.89 mmol) in THF (150 mL) was added DIAD (3.90mL, 19.68 mmol) followed by PPh₃ (5.25 g, 20.038 mmol) at 0° C. and wasstirred at 0° C. for 10 mins. To this mixture was added a solution of1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethan-1-ol (Preparation 135, 3.68mg, 17.89 mmol) in THF (100 mL) at 0° C. and the reaction mixture wasstirred at rt for 16 hr. The reaction was quenched with H₂O andextracted with EtOAc. The combined extracts were washed with water,brine, dried (Na₂SO₄) and evaporated to dryness in vacuo. The residuewas purified by flash chromatography in 20% EtOAc: Hexane to afford thetitle compound as an off white solid (4 g, 48%). LCMS m/z=468.8 [MH]⁺

Preparation 71: 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 g, 3255.84 mmol)and NIS (805.74 g, 3581.43 mmol) in DMF (3.3 L) was stirred at rt for 3hrs. The mixture was poured into ice water (20 L) and resulting solidwas filtered, washed with saturated sodium thiosulphate solution (4×2.5L), water (4×2.5 L) and dried under vacuum to afford the title compoundas an off white solid (780 g, 85.8%). ¹HNMR (400 MHz, DMSO-d₆): 7.94 (s,1H), 8.59 (s, 1H). LCMS m/z=279.6 [MH]⁺

Preparation 72:4-Chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

NaH (60%, 15.74 g, 393.60 mmol) was added portion wise to an ice-cooledsolution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71,100 g, 357.82 mmol) in THF (2.5 L) and the resulting suspension stirredat 0° C. for 1 hr. SEM-CI (69.81 mL, 393.60 mmol) was added drop wiseand the reaction stirred at rt for 16 hrs. The reaction was cooled to 0°C. and quenched with brine solution and the mixture extracted withEtOAc. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by column chromatography on silica gel eluting withEtOAc:Hexane (7:93) to afford the title compound as a white solid (85 g,58.0%). ¹HNMR (400 MHz, DMSO-d₆): 0.10 (s, 9H), 0.82 (t, 2H), 3.51 (t,2H), 5.60 (s, 2H), 8.13 (s, 1H), 8.69 (s, 1H). LCMS m/z=410.0 [MH]⁺

Preparation 73:4-Chloro-5-iodo-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

To a solution of4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 72, 43 g, 105.68 mmol) in THF (500 mL) was added LDA (79.26mL, 158.52 mmol) at −78° C. under N₂. The mixture was stirred at −20° C.for 2 hr re-cooled to −78° C. and Mel (8 mL, 126.82 mmol) added. Thereaction mixture was stirred at −20° C. for 2 hr. The reaction wasquenched with saturated NH₄Cl solution and extracted with EtOAc (3×500mL). The combined organics were washed with water (100 mL), brine (100mL), dried (Na₂SO₄) and evaporated to dryness in vacuo. The residue waspurified by column chromatography (pet. ether/EtOAc 10:1) to give thetitle compound as a yellow solid (10 g, 65%). ¹HNMR (400 MHz, DMSO-d₆):0.11 (s, 9H), 0.83 (t, 2H), 2.54 (s, 3H), 3.47 (t, 2H), 5.70 (s, 2H),8.62 (s, 1H). LCMS m/z=424, 426 [MH]⁺

Preparation 74:5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of4-chloro-5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 75, 5 g, 10.2 mmol) in dioxane (30 mL) was added NH₄OH (100mL) and the reaction was stirred at 120° C. in a sealed tube for 16 hr.The cooled reaction was diluted with ice cold water, the resulting solidfiltered off, washed with water, then hexane and dried under reducedpressure to afford the title compound (12 g, 83.3% for composite batch)as a white solid. ¹HNMR (400 MHz, DMSO-de): 0.10 (s, 9H), 0.76 (m, 2H),3.46 (t, 2H), 5.17 (s, 2H), 5.34 (s, 2H), 6.58 (brs, 2H), 7.45 (s, 1H),7.52 (s, 1H), 7.84 (s, 1H), 8.13 (s, 1H).

Preparation 75:4-chloro-5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine

NaH (60% in oil, 3.4 g, 85.87 mmol) was added to a stirred solution of4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 20 g, 71.56mmol) in DMF (400 mL), followed by4-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (26.49g, 107.34 mmol) and the reaction stirred at rt for 12 hrs. The reactionmixture was diluted with water and EtOAc (250 mL each), the layersseparated and the organic layer was washed with water followed by brinesolution, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel to afford the titlecompound (15.2 g, 43.3%) as a colorless gum. ¹HNMR (400 MHz, DMSO-d₆):0.11 (s, 9H), 0.73 (m, 2H), 3.43 (t, 2H), 5.32 (m, 4H), 7.57 (s, 1H),7.89 (s, 1H), 8.03 (s, 1H), 8.67 (s, 1H). LCMS m/z=489.6 [MH]⁺

Preparation 76:6-Bromo-5-(4-chlorophenyl)-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Propargyl bromide (73.8 mg, 0.5 mmol) was added to a solution of6-bromo-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 78, 107 mg, 0.331 mmol) in DMF (6 mL) and the mixturecooled to 0° C. NaOEt (27 mg, 0.4 mmol) was added and the reactionstirred at rt for 18 hrs. The reaction was diluted with aq. NH₄Cl andextracted with EtOAc (3×50 mL). The combined organic extracts werewashed with 20% LiCl soln., dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography on silica geleluting with EtOAc:heptane (0:100 to 100:0) to afford the title compoundas a beige solid (67 mg, 55.9%). ¹HNMR (400 MHz, CDCl₃): 2.98 (s, 1H),5.04 (br s, 2H), 5.15 (s, 2H), 7.45-7.53 (m, 4H), 8.36 (s, 1H). LCMSm/z=363.0 [MH]⁺

Preparation 77:7-(But-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-4-amine(Preparation 86, 5 g, 16.02 mmol) in EtOH: water (125 mL, 9:1) was added4-chlorophenylboronic acid (3.50 g, 22.43 mmol) followed by Na₂CO₃ (6.79g, 64.08 mmol) and the resulting reaction mixture was degassed withAr_((g)) for 15 mins. Pd(PPh₃)₄ (1.11 g, 0.96 mmol) was added and thereaction was stirred at 90° C. for 5 hrs. The cooled mixture wasfiltered and the filtrate concentrated in vacuo. The residue was dilutedwith water, extracted with DCM, the combined organic extracts dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel eluting with EtOAc:hexane (50:50) toafford the title compound as an off white solid (2.7 g, 56.84%). ¹HNMR(400 MHz, DMSO-d₆): 1.70 (d, 3H), 3.62 (s, 1H), 5.70 (m, 1H), 6.22 (brs,2H), 7.48-7.53 (m, 5H), 8.17 (s, 1H). LCMS m/z=297.0 [MH]⁺

Preparation 78:6-Bromo-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of6-bromo-5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 82, 150 mg, 0.331 mmol) and TBAF (343 mg, 1.24 mmol) in THF(3.3 mL) was heated at 70° C. for 18 hrs. 1M HCl (2 mL) and water (2 mL)were added and the cooled mixture was then basified by the addition ofsat. NaHCO₃. The mixture was extracted with DCM (3×50 mL) and thecombined organic extracts dried (Na₂SO₄) and concentrated under reducedpressure to afford the title compound, which was used without furtherpurification. LCMS m/z=324.9 [MH]⁺

Preparation 79:5-(4-Chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of5-(4-chlorophenyl)-2-methyl-7-{[2-(trimethylsilyl)ethoxy}methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 81, 500 mg, 1.28 mmol) in TFA (3 mL) was stirred at rt for30 min. The solution was diluted with heptane and concentrated in vacuoto remove TFA. The residue was dissolved in MeCN (12 mL), 35% aqueousNH₄OH (6 mL) added to adjust pH to ˜10, the mixture diluted withadditional MeCN and water and the resulting solid filtered off and driedunder vacuum, to afford the title compound as an off white solid, whichwas used without further purification. LCMS m/z=289.0 [MNa]⁺

Preparation 80: 5-(4-Chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

TFA (73.52 mL, 960.13 mmol) was added to an ice cooled stirred solutionof5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 83, 18 g, 48.0 mmol) in DCM (180 mL) and the resultingsuspension stirred at rt for 16 hr. The reaction mixture wasconcentrated in vacuo, diluted with MeOH (80 mL) and treated with EDA(57.75 mL, 480.06 mmol) and the solution stirred for 16 hrs. Thereaction mixture was concentrated and filtered, the resulting solidwashed with water and dried under vacuum to afford the title compound asa white solid (10 g, 85.11%). ¹HNMR (400 MHz, DMSO-d₆): 6.06 (brs, 2H),7.28 (s, 1H), 7.46-7.51 (m, 4H), 8.11 (s, 1H), 11.84 (br s, 1H). LCMSm/z=245.0 [MH]⁺

Preparation 81:5-(4-Chlorophenyl)-2-methyl-7-{[2-(trimethylsilyl)ethoxy}methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

4-Chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine(Preparation 84, 1.1 g, 2.60 mmol) was suspended in NH₄OH (3 mL) anddioxane (1 mL) and the reaction heated at 130° C. under microwaveirradiation for 60 mins. The cooled mixture was concentrated and theresidue suspended in water and stirred for 1 hr. The mixture wasfiltered and dried to give a brown solid. A mixture of this solid, (680mg, 1.68 mmol), 4-chlorophenylboronic acid (312 mg, 1.93 mmol) andNa₂CO₃ (713 mg, 6.73 mmol) was suspended in EtOH (9 mL) and water (1 mL)and degassed for 5 mins. Pd(PPh₃)₄ (97.1 mg, 0.084 mmol) was added andthe reaction heated to 90° C. for 18 hrs. The cooled reaction wasdiluted with water, extracted with EtOAc and the organic phase washedwith brine and dried (MgSO₄), filtered and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with 50-100% EtOAc: heptane to afford the title compound as asolid (500 mg, 49.4%). LCMS m/z=390.1 [MH]⁺

Preparation 82:6-Bromo-5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To the stirred solution of5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 83, 500 mg, 1.334 mmol) in DMF (20 mL) was added NBS (284.8mg, 1.6 mmol) and the reaction stirred at rt for 5 hrs. The reaction wasdiluted with water, extracted with EtOAc and the combined organicextracts washed with water followed by brine, dried (Na₂SO₄) andconcentrated under reduced pressure to afford the title compound as anoff white solid (500 mg, 82.62%). ¹HNMR (400 MHz, DMSO-d₆): 0.08 (s,9H), 0.85 (t, 2H), 3.58 (t, 2H), 5.60 (s, 2H), 6.09 (br s, 2H), 7.42 (d,2H), 7.58 (d, 2H), 8.18 (s, 1H). LCMS m/z=454.8 [MH]⁺

Preparation 83:5-(4-Chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 33, 25 g, 64.05 mmol) in EtOH:water (620 mL, 9:1) was added4-chlorophenylboronic acid (14.02 g, 89.68 mmol) followed by Na₂CO₃(27.15 g, 256.21 mmol) and the mixture degassed with Ar for 15 mins.Pd(PPh₃)₄ (4.44 g, 3.84 mmol) was added and the reaction stirred at 90°C. for 5 hrs. The cooled mixture was filtered, the filtrate concentratedand the residue diluted with water and extracted with DCM. The combinedorganic layers were dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel eluting withEtOAc:hexane (40:60) to afford the title compound as an off white solid(18 g, 74.94%). ¹HNMR (400 MHz, DMSO-d₆) 0.08 (s, 9H), 0.84 (t, 2H),3.55 (t, 2H), 5.53 (s, 2H), 6.21 (br s, 2H), 7.46-7.53 (m, 5H), 8.18 (s,1H). LCMS m/z=451.0 [MH]⁺

Preparation 84:4-Chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine(1.7 g, 5.79 mmol) in DMF (25 mL) was slowly added 60% NaH dispersion(0.290 g, 7.24 mmol) and the mixture stirred for 15 mins under Ar.SEM-CI (1.28 mL, 7.24 mmol) was added in portions over 5 mins and thereaction stirred at rt for 18 hrs. Sat. aq. sodium bicarbonate (25 mL)was added and the mixture extracted with EtOAc. The organic extractswere dried (MgSO₄) and concentrated under reduced pressure to afford thetitle compound as an oil (1.1 g, 44.9%), which was used without furtherpurification. ¹HNMR (400 MHz, MeOD-d₄): −0.05 (s, 9H), 0.89 (t, 2H),2.71 (s, 3H), 3.59 (t, 2H), 5.63 (s, 2H), 7.78 (s, 1H). LCMS m/z=423.9[MH]⁺

Preparation 85:5-Iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of4-chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 90, 8 g, 0.025 mol) and aqueous NH₄OH solution (30%, 100mL) in 1,4-dioxane (45 mL) was heated to 90° C. for 4 hr followed by afurther 16 hr at rt. The reaction mixture was filtered and washed withEtOAc (15 mL) to afford the title compound (6.8 g, 90%). ¹HNMR (400 MHz,DMSO-d₆) 3.57 (s, 1H), 4.95 (s, 2H), 6.66 (br s, 2H), 7.52 (s, 1H), 8.13(s, 1H). LCMS m/z=299.0 [MH]⁺

Preparation 86:7-(But-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 91, 28 g, 84.45 mmol) in dioxane (120 mL) was added NH₄OH(400 mL) and the reaction stirred at 120° C. in a sealed tube for 16 hr.The cooled mixture was filtered, the solid washed with water followed by50% EtOAc-Hexane and dried in vacuo to afford the title compound as anoff-white solid (20 g, 75.87%). ¹HNMR (400 MHz, DMSO-d₆) 1.63 (d, 3H),3.51 (d, 1H), 5.61 (m, 1H), 6.67 (br s, 2H), 7.60 (s, 1H), 8.12 (s, 1H).LCMS m/z=312.8 [MH]⁺

Preparation 87:5-Iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of4-chloro-5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 92, 350.0 g, 1.012 mol) in dioxane (1.75 L) was addedNH₃.H₂O (5.0 L) and the reaction stirred at 80° C. in an autoclave (10L) for 10 hrs. The cooled reaction mixture was filtered and dissolved inEtOAc (7.0 L). The solution was washed with brine (2×5.0 L), dried(Na₂SO₄), and concentrated in vacuo. The crude solid was triturated(pet. ether:EtOAc=3.0 L300.0 mL) for 24 hrs, filtered and dried toafford the title compound as a brown solid (200.0 g, 60.61%). ¹HNMR (400MHz, CDCl₃): 0.97 (t, 3H), 1.96-2.02 (m, 2H), 2.50 (d, 1H), 5.55 (m,1H), 5.76 (brs, 2H), 7.33 (s, 1H), 8.26 (s, 1H).

Preparation 88:5-Iodo-7-(1-cyclopropylprop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as a light yellow solid (1.8 g 65%) from4-chloro-7-(1-cyclopropylprop-2-yn-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 93), following the procedure described in preparation 85.¹HNMR (400 MHz, DMSO-d₆) 0.38 (m, 1H), 0.48 (m, 1H), 0.61-0.66 (m, 2H),1.54 (m, 1H), 3.53 (s, 1H), 5.17 (m, 1H), 7.60 (s, 1H), 8.10 (s, 1H).LCMS m/z=338.8 [MH]⁺

Preparation 89:5-Iodo-2-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of4-chloro-5-iodo-2-methyl-7-prop-2-ynyl-7H-pyrrolo[2,3-d]pyrimidine(Preparation 94, 10 g, 30.21 mmol) in 1,4-dioxane (40 mL) was addedammonium hydroxide solution (75 mL) in a sealed tube and the reactionstirred at 110° C. for 10 hr. The reaction volume was reduced to half ofits original volume and cooled. A solid precipitated and was collectedby filtration, washed with Et₂O and dried to afford the title compoundas an off-white solid (4.8 g, 50.9%). ¹HNMR (400 MHz, DMSO-d₆) 2.39 (s,3H), 3.38 (s, 1H), 4.92 (s, 2H), 6.57 (brs, 2H), 7.39 (s, 1H). LCMSm/z=312.9 [MH]⁺

Preparation 90:4-Chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(155 g, 0.554 mol) in DMF (750 mL) was added NaOEt (21% in EtOH, 215.7g, 0.665 mol) solution at rt the mixture stirred for 10 min, then cooledto 0° C. Propargyl bromide (80% solution in toluene, 123.7 g, 0.831 mol)was added drop wise and the reaction stirred at rt for 16 hr. Themixture was diluted with cold water (1 L), the resulting suspensionfiltered and washed with water followed by hexane (2×200 mL) and driedunder reduced pressure to afford the title compound as a light yellowsolid (162 g, 92.5%). ¹HNMR (400 MHz, DMSO-d₆) 3.49 (s, 1H), 5.14 (s,2H), 8.05 (s, 1H), 8.69 (s, 1H). LCMS m/z=318.0 [MH]⁺

Preparation 91:7-(But-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (80g, 286.26 mmol) in DMF (1 L) was added K2CO₃ (79.12 g, 572.51 mmol)followed by but-3-yn-2-yl methanesulfonate (63.62 g, 429.38 mmol) andthe reaction stirred at 80° C. for 16 hrs. The reaction was cooled to 0°C. and diluted with water. The resulting solid was filtered off, washedwith ether and dried in vacuo to afford the title compound, as a yellowsolid (49 g, 51.63%). ¹HNMR (400 MHz, CDCl₃) 1.70 (d, 3H), 2.54 (d, 1H),5.78 (m, 1H), 7.69 (s, 1H), 8.61 (s, 1H). LCMS m/z=331.6 [MH]⁺

Preparation 92:4-Chloro-5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

K₂CO₃ (296.72 g, 2146.92 mmol) and pent-1-yn-3-yl methansulfonate(Preparation 138, 313.4 g, 1932.22 mmol) were added to a solution of4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 300 g,1073.46 mmol) in DMF (2500 mL) cooled to 5° C., and the reaction mixturestirred at 80° C. for 5 hrs. Water (4 L) was added to the cooled mixtureand stirred at rt for 2 hrs. The resulting solid material was filteredoff, washed with water (3 L), 10% EtOAc:hexane, diethyl ether (500 mL)and dried to afford the title compound as an off white solid (190 g,57.2%). ¹HNMR (400 MHz, CDCl₃) 0.97 (t, 3H), 1.96-2.09 (m, 2H), 2.55 (s,1H), 5.61 (m, 1H), 7.66 (s, 1H), 8.60 (s, 1H). LCMS m/z=345.9 [MH]⁺

Preparation 93:4-Chloro-7-(1-cyclopropylprop-2-yn-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(9.0 g, 34.61 mmol) in DMF (75 mL) at 0-5° C. was added CS₂CO₃ (33.75 g,103.8 mmol) followed by (1-chloroprop-2-yn-1-yl)cyclopropane (9.91 g,86.53 mmol and the reaction stirred at rt for 16 hrs. The reactionmixture was diluted with water and extracted with EtOAc, the combinedorganic phases washed with water, dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel to afford the title compound as an offwhite solid (6.5 g, 38%). ¹HNMR (400 MHz, DMSO-d₆) 0.38 (m, 1H), 0.53(m, 1H), 0.65-0.76 (m, 2H), 1.62-1.69 (m, 1H), 3.62 (s, 1H), 5.31 (m,1H), 8.18 (s, 1H), 8.67 (s, 1H). LCMS m/z=357.8 [MH]⁺

Preparation 94:4-chloro-5-iodo-2-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine(10 g, 34.13 mmol) in DMF (55 mL) was added sodium ethoxide solution(19.177 mL, 51.195 mmol. 2.67M in ethanol) followed by, propargylbromide (4.56 mL, 51.19 mmol) at 0° C. and the resulting mixture stirredat room temperature for 16 hr. The reaction mixture was diluted withEtOAc, washed with water, brine, dried (Na₂SO₄) and evaporated todryness in vacuo. The residue was purified by column chromatography (2%EtOAc in hexane) to afford the title compound as an off-white solid (4g, 35.34%). ¹HNMR (400 MHz, CDCl₃) 2.73 9s, 3H), 5.00 (s, 2H), 7.50 (s,1H). LCMS m/z=332 [MH]⁺

Preparation 95:4-chloro-7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of4-chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 90, 48 g, 151.17 mmol) in toluene: t-BuOH (1000 mL, 4:1)was added CuI (15.83 g, 83.14 mmol) and DIPEA (263.3 mL, 1511.72 mmol)and the reaction mixture stirred for 10 min at rt.1-Azido-2-fluorobenzene (Preparation 145, 31.09 g, 226.76 mmol) wasadded at 0° C. and the resulting mixture stirred at rt for 48 hrs. Thereaction mixture was diluted with water and aqueous ammonia andextracted with EtOAc. The combined extracts were washed with water,brine, dried (Na₂SO₄) and evaporated to dryness in vacuo. The residuewas triturated with 20% EtOAc-Hexane to afford the title compound as anoff white solid (38 g, 55.3%). ¹HNMR (400 MHz, DMSO-d₆) 5.68 (s, 2H),7.42 (t, 1H), 7.57 (m, 2H), 7.80 (t, 1H), 8.11 (s, 1H), 8.63 (s, 1H),8.69 (s, 1H). LCMS m/z=455 [MH]⁺

Preparation 96:2-Amino-4-(4-chlorophenyl)-1-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-1H-pyrrole-3-carbonitrile

1-Azido-2-fluorobenzene (Preparation 145, 38 mg, 0.26 mmol), CuI (19 mg,0.10 mmol) and Hunig's base (0.31 mL, 1.8 mmol) were added to2-amino-4-(4-chlorophenyl)-1-[2-methylbut-3-yn-2-yl]-1H-pyrrole-3-carbonitrile(Preparation 97, 50 mg, 0.18 mmol) in toluene (2.5 mL) and tBuOH (0.6mL) under N₂ and the reaction stirred at rt for 4 hrs. The mixture waspoured into water, extracted twice with EtOAc, the combined organicextracts dried (MgSO₄), filtered, and evaporated under reduced pressure.The crude product was purified by column chromatography on silica geleluting with EtOAc:heptane (20:80 to 80:20) to afford the title compoundas a dark green oil (78.4 mg, 71.7%). LCMS m/z=421.4 [MH]⁺

Preparation 97:2-Amino-4-(4-chlorophenyl)-1-[2-methylbut-3-yn-2-yl]-1H-pyrrole-3-carbonitrile

Malononitrile (187 mg, 2.8 mmol) was added to4-chloro-N-(2-methylbut-3-yn-2-yl)benzamide (587 mg, 2.1 mmol) in MeOH(10 mL) and the solution degassed under N₂ while cooling in an ice/waterbath. KOH (336 mg, 5.93 mmol) in water (1.5 mL) was added drop wise andthe reaction then stirred at 65° C. for 1 hr. The cooled mixture waspoured into water, extracted with EtOAc (3×), the combined organicextracts dried (MgSO₄), filtered and concentrated in vacuo. Theresulting brown oil was purified by column chromatography on silica geleluting with EtOAc:heptane (20:80 to 80:20) to afford the title compoundas a dark yellow oil (288 mg, 48.4%). ¹HNMR (400 MHz, CDCl₃) 1.85 (s,6H), 2.68 (s, 1H), 4.72 (s, 2H), 6.46 (s, 1H), 7.32 (d, 2H), 7.52 (d,2H). LCMS m/z=284.3 [MH]⁺

Preparation 98: 4-(chloromethyl)-1-(2-fluorophenyl)-1H-pyrazole

To a solution of (1-(2-fluorophenyl)-1H-pyrazol-4-yl)methanol(Preparation 99, 20 g, 130.2 mmol) in DCM (200 mL) was added SOCl₂ (45.3mL, 625 mmol) drop wise at 0° C. After the addition was complete, thereaction was stirred at rt for 4 hr. The mixture was concentrated invacuo to afford the title product (20 g, 99%) as a dark brown oil whichwas used directly in the next step without further purification. ¹HNMR(400 MHz, CDCl₃) 4.62 (s, 2H), 7.22-7.36 (m, 3H), 7.83 (s, 1H),7.88-7.92 (m, 1H), 8.05 (d, 1H).

Preparation 99: (1-(2-fluorophenyl)-1H-pyrazol-4-yl)methanol

To a mixture of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (20.0 g,131.6 mmol) and MeOH (200 mL) was added NaBH₄ (12 g, 315.6 mmol) inseveral portions at 0° C. After the addition was completed, the mixturewas stirred at rt for 2 hrs. The reaction was carefully quenched withwater (100 mL) at 0° C. The mixture was extracted with EtOAc (200 mL×3),dried (Na₂SO₄), and concentrated in vacuo to give the title compound (20g, 99%) as a brown solid. ¹HNMR (400 MHz, CDCl₃) 2.02 (brs, 1H), 4.68(s, 2H), 7.20-7.31 (m, 3H), 7.75 (s, 1H), 7.87 (m, 1H), 8.00 (d, 1H).LCMS m/z=193.1 [MH]⁺

Preparation 100: 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole

SOCl₂ (2 mL) was added slowly to a solution of1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propan-1-ol (Preparation 101, 0.5g, 2.42 mmol) in DCM (20 mL) and stirred at rt for 3 hrs. The reactionwas evaporated to dryness in vacuo to afford the title compound (0.58 g,100%). ¹HNMR (400 MHz, CDCl₃) 1.09 (t, 3H), 2.15 (m, 2H), 4.95 (t, 1H),7.20-7.30 (m, 3H), 7.74 (s, 1H), 7.87 (m, 1H), 8.00 (s, 1H). LCMSm/z=235.1 [MH]⁺

Preparation 101: 1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propan-1-ol

To a solution of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g,15.8 mmol) in THF (50 mL) was added EtMgBr (31.6 mL, 31.6 mmol) dropwise at 0° C. and the reaction stirred at rt for 2 hrs. Water was addedto quench the reaction and the mixture extracted with EtOAc. The organiclayer was collected, washed with brine, dried and evaporated. The crudeproduct was purified by column chromatography on silica gel eluting withDCM:MeOH (95:5) to afford the title compound (3 g, 86%). ¹HNMR (400 MHz,CDCl₃) 1.00 (t, 3H), 1.88 (m, 2H), 4.71 (m, 1H), 7.19-7.27 (m, 3H), 7.71(s, 1H), 7.87 (m, 1H), 7.95 (s, 1H). LCMS m/z=221.2 [MH]⁺

Preparation 102: (1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)methanol

To a solution of 1-(2,4-difluorophenyl)-1H-pyrazole-4-carbaldehyde (0.7g, 3.365 mmol) in MeOH (20 mL) was added NaBH₄ (0.32 g, 8.43 mmol) dropwise at 0° C. Cooling was removed and the reaction mixture stirred for30 min at rt. The mixture was quenched with water, extracted with EtOAc(150 mL×2). The combined extracts were washed with brine (2×100 mL),dried (Na₂SO₄) and evaporated in vacuo to give the title compound (0.70g, 99%) as an oil. ¹HNMR (400 MHz, DMSO-d₆) 4.45 (d, 2H), 5.02 (t, 1H),7.24 (t, 1H), 7.53 (t, 1H), 7.72 (s, 1H), 7.80 (m, 1H), 8.04 (s, 1H).LCMS m/z=211.1 [MH]⁺

Preparation 103: 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-ol

To a solution of 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one(1.5 g, 6.35 mmol) in MeOH (60 mL) was added NaBH₄ (360 mg, 9.52 mmol)at 0° C. and the reaction mixture was stirred at rt for 2 hr. Thereaction was quenched with 1N HCl (2 mL), the solvent evaporated underreduced pressure and the residue partitioned between EtOAc (20 mL) andwater (30 mL). The aqueous phase was extracted with EtOAc (20 mL×2) andthe combined extracts dried (Na₂SO₄) and evaporated to dryness in vacuo.The residue was purified by silica gel chromatography eluting with MeOHin DCM from 0 to 15% in 20 mins to give the title compound (1.0 g, 66%)as a red oil. ¹HNMR (400 MHz, DMSO-d₆) 0.88 (t, 3H), 1.67 (q, 2H), 4.50(q, 1H), 5.04 (d, 1H), 7.24 (m, 1H), 7.53 (m, 1H), 7.58 (s, 1H), 7.80(m, 1H), 7.99 (s, 1H). LCMS m/z=239.2 [MH]⁺

Preparation 104: 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one

Step 1: A degassed mixture of(E)-2-(ethoxymethylene)-3-oxopentanenitrile (Australian. J. Chem. 44(9)1263-73; 1991; 6 g, 39.17 mmol), Et₃N (11.89 g, 117.5 mmol) and(2,4-difluorophenyl)hydrazine hydrochloride (10.61 g, 58.75 mmol) inEtOH (200 mL) was heated at reflux for 2 hrs under an atmosphere of N₂.The reaction was cooled to rt and the solvent was removed under reducedpressure to give a residue. The crude product was purified by columnchromatography on silica gel eluting with pet. ether:EtOAc (10:1 to 1:1)to afford the1-(5-amino-1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one as ayellow oil (5 g, 50.8%). LCMS m/z=252.1 [MH]⁺

Step 2: To a mixture of1-(5-amino-1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one (5 g,19.9 mmol) in THF (150 mL) was added drop wise tert-butyl nitrite (4.1g, 39.8 mmol) at rt and the reaction stirred at 65° C. for 4 hours. Thesolvent was evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel eluting with pet.ether:EtOAc (10:1 to 1:1) to afford the title compound as a yellow oil(2 g, 42.54%). ¹HNMR (400 MHz, MeOD-d₄) 1.19 (t, 3H), 2.92 (q, 2H), 7.18(m, 1H), 7.27 (m, 1H), 7.84 (m, 1H), 8.20 (s, 1H), 8.65 (s, 1H). LCMSm/z=237.1 [MH]⁺

Preparation 105: 5-(chloromethyl)-2-(2-fluorophenyl)-1H-imidazole

(2-(2-Fluorophenyl)-1H-imidazol-5-yl)methanol (Preparation 110, 100 mg,0.52 mmol) was heated with SOCl₂ (0.075 mL, 1.041 mmol) at 80° C. for 3hrs. The reaction mixture was evaporated to dryness in vacuo and theresidue dissolved in CHCl₃ and evaporated to dryness to afford the titlecompound as a brown solid (80 mg, 73%). ¹HNMR (400 MHz, DMSO-d₆) 4.90(s, 2H), 7.42-7.57 (m, 2H), 7.68 (m, 1H), 7.80 (s, 1H), 8.02 (m, 1H).LCMS m/z=175 [M-Cl]⁺

Preparation 106: 5-(chloromethyl)-2-phenyl-1H-imidazole

The title compound was prepared as an off-white solid (312 mg, 93%), inan analogous way to Preparation 105 from(2-phenyl-1H-imidazol-5-yl)methanol (Preparation 107). ¹HNMR (400 MHz,DMSO-d₆) 4.93 (s, 2H), 7.64-7.66 (m, 3H), 7.86 (s, 1H), 8.18-8.21 (m,2H).

Preparation 107: (2-phenyl-1H-imidazol-5-yl)methanol

The title compound was prepared an off white solid (3.6 g, 43%) in ananalogous way to Preparation 110 from benzamidine hydrochloride. Thecompound was used without purification in Preparation 106. ¹HNMR (400MHz, DMSO-d₆) 4.43 (s, 2H), 4.87-5.06 (m, 1H), 6.91-7.04 (m, 1H), 7.32(m, 1H), 7.40 (m, 2H), 7.91 (m, 2H), 12.31-12.44 (m, 1H). LCMS m/z=175.0[MH]⁺

Preparation 108: 4-(chloromethyl)-1-(2-fluorophenyl)-1H-imidazole

To a stirred solution of (1-(2-fluorophenyl)-1H-imidazol-4-yl)methanol(Preparation 109, 80 mg, 0.416 mmols) in DCM (1 mL) was added SOCl₂(0.06 mL, 0.833 mmol) at 0° C. The resulting solution was heated toreflux for 16 hrs. The reaction mixture was concentrated under reducedpressure to afford the title compound (80 mg, 91.24%) as an off whitesolid. ¹HNMR (400 MHz, DMSO-d₆) 4.83 (s, 2H), 7.40-7.78 (m, 5H), 7.93(s, 1H).

Preparation 109: (1-(2-fluorophenyl)-1H-imidazol-4-yl)methanol

Borane-THF complex (1M solution) was added drop wise to a stirredsolution of 1-(2-fluorophenyl)-1H-imidazole-4-carboxylic acid (300 mg,1.46 mmol) in THF (2 mL) at rt and heated to reflux for 2 hrs followedby stirring at rt for 16 hrs. The reaction mixture was cooled to 0° C.and MeOH (1.5 mL) was added drop wise and the mixture was evaporated todryness. The residue was dissolved in 1.5 mL 2N HCl solution andrefluxed for 2 hr, cooled to 0° C. and treated drop wise with 2 mL 2NNaOH solution. The solid was removed by filtration and dried to affordthe title compound as an off white solid (250 mg, 89%). ¹HNMR (400 MHz,DMSO-d₆) 4.21 (d, 2H), 4.99 (t, 1H), 7.32-7.52 (m, 4H), 7.63 (t, 1H),7.96 (s, 1H). LCMS m/z=193 [MH]⁺

Preparation 110: (2-(2-fluorophenyl)-1H-imidazol-5-yl)methanol

A suspension of 2-fluoro-benzamidine hydrochloride (3 g, 17.18 mmol),1,3-dihydroxy-propan-2-one (3.17 g, 35.22 mmol), and NH₄Cl (4.2 g) inNH₄Cl (30 mL) was heated at 80° C. for 1 hr. The reaction mixture wasextracted with EtOAc (50 mL×3), washed with brine, dried (Na₂SO₄) andevaporated in vacuo to give a solid that was purified by columnchromatography on silica gel eluting with 2% methanol in DCM to affordthe title compound as an off-white solid (2.2 g, 66.6%). ¹HNMR (400 MHz,DMSO-d₆, 100° C.) 4.50 (s, 2H), 7.01 (s, 1H), 7.25 (m, 2H), 7.38 (m,1H), 7.99 (m, 1H). LCMS m/z=175 [M-Cl]⁺

Preparation 111:4-(1-chloropropyl)-1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole

To a solution of1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-ol(Preparation 112, 2.8 g, 11.1 mmol) in DCM (80 mL) was added SOCl₂ (2.64g, 22.2 mmol) at 0° C. and the reaction mixture stirred at 40° C. for 5hr. The reaction mixture was evaporated to dryness to give the titlecompound as a yellow solid (2.4 g, 80%). ¹HNMR (400 MHz, CDCl₃) 1.11 (t,3H), 2.30 (s, 3H), 2.38 (m, 2H), 5.07 (t, 1H), 7.08 (m, 2H), 7.53 (m,1H). LCMS m/z=272.1 [MH]⁺

Preparation 112:1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-ol

To a solution of1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-one(Preparation 113, 1.24 g, 4.94 mmol) in MeOH (25 mL) was added NaBH₄(374 mg, 9.88 mmol) at 0° C. and the reaction mixture stirred at rt for3 hr. The mixture was quenched with 1N HCl and concentrated in vacuo.The residue was diluted with EtOAc (50 mL), washed with brine (30 mL),dried (Na₂SO₄) and evaporated to dryness in vacuo. The residue waspurified by combi-flash eluting with EtOAc in pet. ether (10-70%) toafford the title compound as a white solid (1.1 g, 88%). ¹HNMR (400 MHz,MeOD-d₄) 1.01 (t, 3H), 2.02 (m, 2H), 2.31 (s, 3H), 4.81 (t, 1H), 7.29(m, 1H), 7.40 (m, 1H), 7.65 (m, 1H). LCMS m/z=254.1 [MH]⁺

Preparation 113:1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-one

Step 1: To a stirred solution of1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (7g, 29.3 mmol) in DCM (150 mL) was added HATU (22.3 g, 58.6 mmol) andDIPEA (11.34 g, 87.9 mmol) simultaneously at 0-5° C. under N₂ and thesolution stirred for 15 min. N,O-Dimethylhydroxylamine (3.7 g, 38 mmol)was added and the reaction stirred at rt for 16 hr. The reaction mixturewas diluted with water (150 mL) and extracted with DCM (150 mL×2). Thecombined organic layers were washed with brine (100 mL), dried (Na₂SO₄)and concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel chromatography eluting with EtOAc inpet. ether (20-70%) to afford1-(2,4-difluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide(7.6 g) as a light solid.

Step 2: To a solution of1-(2,4-difluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide(Step 1, 2 g, 7.09 mmol) in THF (25 mL) was added EtMgBr (1.42 mL, 14.2mmol, 1M) at 0° C. under N₂ and stirred at rt for 3 hr. The reaction wasquenched with NH₄Cl solution (20 mL) and extracted with EtOAc (100mL×2). The combined organics were washed with brine (50 mL), dried(Na₂SO₄) and evaporated to dryness in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with EtOAc in pet. ether(10-70%) to give the title compound as a white solid (1.24 g, 69%).¹HNMR (400 MHz, CDCl₃) 1.19 (t, 3H), 2.44 (s, 3H), 3.16 (q, 2H), 7.06(m, 2H), 7.42 (m, 1H). LCMS m/z=252.2 [MH]⁺

Preparation 114:4-(1-chloroethyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole

To a solution of1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanol(Preparation 115, 650 mg, 2.94 mmol) in DCM (10 mL) was added SOCl₂ (699mg, 5.88 mmol) at 0° C. Then the reaction mixture was stirred at rt for3 hr. and evaporated to dryness to afford the title compound as a yellowsolid (600 mg, 85%). LCMS m/z=240.1 [MH]⁺

Preparation 115:1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethan-1-ol

Step 1: To a solution of1-(2-fluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide(Preparation 116, 900 mg, 3.4 mmol) in THF (30 mL) was added CH₃MgBr(2.3 mL, 6.8 mmol) at 0° C. and the reaction stirred at rt for 2 hrs.The reaction mixture was quenched with ammonium chloride solution (20mL) and extracted with EtOAc (30 mL×2). The combined organics werewashed with brine (50 mL), dried (Na₂SO₄) and evaporated to dryness invacuo to afford1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethan-1-one (700mg, 94%) which was used in Step 2 without further purification. LCMSm/z=220.1 [MH]⁺

Step 2: To a solution of1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (700 mg,3.2 mmol) in MeOH (20 mL) was added NaBH₄ (182 mg, 4.8 mmol) at 0° C.and the reaction mixture stirred at rt for 2 hr. The reaction mixturewas quenched with 1N HCl and the solvent removed in vacuo. The residuewas extracted with EtOAc (20 mL), washed with brine (10 mL), dried(Na₂SO₄) and evaporated to dryness in vacuo. The residue was purified bycombi-flash eluting with 10-50% EtOAc in pet. ether to afford the titlecompound as an off-white solid (650 mg, 91%). LCMS m/z=222.1 [MH]⁺

Preparation 116:1-(2-fluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(Preparation 117, 5 g, 22.6 mmol) in DCM (80 mL) was added HATU (12.88g, 33.9 mmol) and DIPEA (12 mL, 67.8 mmol) simultaneously at 0-5° C.under N₂ and stirred for 20 min. N,O-dimethylhydroxylamine (3.3 g, 33.9mmol) was added and the reaction stirred at rt for 14 hr. The reactionmixture was diluted with water (50 mL) and extracted with DCM (100mL×2). The combined organic extracts were washed by brine (100 mL),dried (Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with EtOAc in pet. ether(20-60%) to afford the title compound as a white solid (4.8 g, 80%).LCMS m/z=265.1 [MH]⁺

Preparation 117:1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

LiOH (1.68 g, 70.2 mmol) was added to a solution of methyl1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (Preparation118, 5.5 g, 23.4 mmol) in MeOH/H₂O (30 mL/10 mL) and the reactionstirred at rt for 3 hr. The solvent was removed in vacuo and the residuetreated with 1N HCl. The resulting solid was collected by filtration,washed with water (20 mL) and dried to give the title compound as awhite solid (5 g, 96%). ¹HNMR (400 MHz, DMSO-d₆) 2.41 (s, 3H), 7.50 (m,1H), 7.61 (m, 1H), 7.71-7.76 (m, 2H), 13.25 (br s, 1H). LCMS m/z=222.1[MH]⁺

Preparation 118: methyl1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate

1-Azido-2-fluorobenzene (Preparation 145, 7.13 g, 52 mmol) and methyl3-oxobutanoate (6 g, 52 mmol) were added to a suspension of milled K2CO₃(14.35 g, 104 mmol) in DMSO (100 mL) and the reaction stirred at rt for14 hr. The reaction mixture was poured into water (50 mL) and the solidcollected, washed with water (50 mL) and diethyl ether (20 mL) to givethe title compound as an off-white solid (5.5 g, 44.7%). ¹HNMR (400 MHz,DMSO-d₆) 2.42 (s, 3H), 3.89 (s, 3H), 7.50 (m, 1H), 7.61 (m, 1H),7.71-7.77 (m, 2H). LCMS m/z=236.1 [MH]⁺

Preparation 119: 4-(1-chloropropyl)-1-phenyl-1H-1,2,3-triazole

SOCl₂ (0.23 mL, 3.171 mmol) was added to solution of1-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-1-ol (Preparation 120, 200 mg,1.057 mmol) in DCM (10 mL) at 0° C. and the reaction mixture heatedunder reflux for 3 hr. The reaction mixture was evaporated to dryness toafford the title compound (200 mg, 85.4%) which was used without furtherpurification. ¹HNMR (400 MHz, DMSO-d₆) 1.03 (t, 3H), 2.15-2.30 (m, 2H),5.31 (t, 1H), 7.50 (t, 1H), 7.61 (t, 2H), 7.91 (d, 2H).

Preparation 120: 1-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-1-ol

To a stirred solution of 1-pentyn-3-ol (1 g, 11.89 mmol) in toluene:t-BuOH (4:1, 28 mL) was added CuI (1.24 g, 6.538 mmol) and DIPEA (20.7mL, 118.88 mmol). The reaction mixture was stirred for 10 min at roomtemperature followed by phenylazide (Preparation 143, 2.61 g, 21.40mmol) at 0° C. and the resulting reaction mixture stirred at roomtemperature for 18 hrs. The reaction mixture was diluted with aq NH₄OHand extracted with EtOAc. The combined organics were washed with water,brine, dried (Na₂SO₄) and evaporated to dryness under reduced pressure.The residue was purified by flash chromatography to afford the titlecompound as an off-white solid (1.3 g, 53.7%). ¹HNMR (400 MHz, DMSO-d₆)0.91 (t, 3H), 1.73-1.89 (m, 2H), 4.67 (m, 1H), 5.34 (d, 1H), 7.47 (t,1H), 7.58 (t, 2H), 7.91 (d, 2H), 8.63 (s, 1H). LCMS m/z=204.4 [MH]⁺

Preparation 121:3-(chloromethyl)-5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

To a stirred solution of3-(chloromethyl)-5-(2-fluorophenyl)-4H-1,2,4-triazole (Preparation 123,400 mg, 1.896 mmol) in DCM (40 mL) was added SEM-CI (1.009 mL, 5.687mmol) drop wise at 0° C. The reaction was stirred for 10 min and Et₃N(1.056 mL, 7.583 mmol) added drop wise at 0° C. and stirred at rt for 8hr. The reaction was quenched with ice-cold water and basified withaq.NaHCO₃ solution. The two layers were separated and the aqueous layerextracted with DCM (40 mL). The combined organics were dried (Na₂SO₄)and evaporated under reduced pressure. The residue was purified by flashchromatography using 10-15% EtOAc in hexane to afford the title compoundas a colorless oily liquid (180 mg, 27.77%, mixture of two isomers).LCMS m/z=342 [MH]⁺

Preparation 122:3-(chloromethyl)-5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

The title compound was prepared in an analogous method to Preparation121 using 3-(chloromethyl)-5-phenyl-4H-1,2,4-triazole (300 mg, 1.554mmol) to afford the title compound (160 mg, 31.78%, mixture of twoisomers). LCMS m/z=324 [MH]⁺

Preparation 123: 3-(chloromethyl)-5-(2-fluorophenyl)-4H-1,2,4-triazolehydrochloride

Step 1: A solution of ethyl (Z)-2-amino-2-(2-(2-fluorobenzoyl)hydrazono)acetate (Preparation 143, 6.2 g, 24.484 mmol) in n-butanol (50 mL) wasstirred at 180° C. for 24 hr. The reaction was evaporated to dryness invacuo and the residue purified by flash chromatography (silica gel,10-20% EtOAc in Hexane) to afford mixture of ethyl5-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate and butyl5-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate as an off-white solid(2.5 g, 43%) which was used in Step 2. LCMS m/z=236.0, 264.0 [MH]⁺

Step 2: To a stirred suspension of LAH (1.297 g, 34.185 mmol) in dry THF(140 mL) was added drop wise a solution of the compound of Step 1 (6 g,22.79 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was stirredat 0° C. for 1 hr and at rt for 1 hr. The reaction mixture was cooled to0° C. and quenched by Fischer workup (1.3 mL H₂O+1.3 mL 15% NaOH+2.6 mLH₂O), and the solids filtered through a Celite® bed. The combinedfiltrates were concentrated under reduced pressure and the residuepurified by column chromatography on silica gel using 3-5% MeOH in DCMto afford (5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)methanol as a yellowsolid (1.07 g, 24%). ¹HNMR (400 MHz, DMSO-d₆, 100° C.) 4.64 (s, 2H),5.20 (br s, 1H), 7.29 (br s, 2H), 7.45 (br s, 1H), 7.97 (t, 1H), 13.70(br s, 1H). LCMS m/z=194 [MH]⁺

Step 3: (5-(2-Fluorophenyl)-4H-1,2,4-triazol-3-yl)methanol (Step 2, 350mg, 1.81 mmol) was dissolved in SOCl₂ (48 mmol, 3 mL) and heated to 80°C. for 1.5 hrs. The cooled reaction mixture was evaporated to dryness invacuo and the residue azeotroped several times with toluene to affordthe title compound as a light yellow solid (450 mg, 100%). ¹HNMR (400MHz, DMSO-d₆) 4.82 (s, 2H), 7.33-7.43 (m, 2H), 7.54 (m, 1H), 7.99 (m,1H). LCMS m/z=212.2 [MH]⁺

Preparation 124: 5-(1-chloroethyl)-3-(2-methoxyphenyl)isoxazole

SOCl₂ (0.11 mL, 1.60 mmol) was added to a stirred solution of1-(3-(2-methoxyphenyl)isoxazol-5-yl)ethan-1-ol (Preparation 125, 100 mg,0.46 mmol) in DCM (3 mL) and heated under reflux for 4 hrs. The reactionmixture was evaporated to dryness in vacuo under N₂ to afford the titlecompound (107 mg) which was used without further purification. ¹HNMR(400 MHz, MeOD-d₄) 1.87 (d, 3H), 3.88 (s, 3H), 5.59 (m, 1H), 6.96-7.75(m, 5H). LCMS m/z=237.6 [MH]⁺

Preparation 125: 1-(3-(2-methoxyphenyl)isoxazol-5-yl)ethan-1-ol

Step 1: NH₂OH.HCl (612 mg, 8.814 mmol) was added to a stirred solutionof 2-methoxybenzaldehyde (1 g, 7.35 mmol) and KOH (989 mg, 17.63 mmol)in water (5 mL) and the reaction heated to 70° C. for 2 hr. The reactionmixture was acidified to pH 3 with 2N HCl at 0 C, and extracted withEtOAc (50 mL×3). The combined organics were washed with water (20 mL×2),brine, dried (Na₂SO₄) and evaporated to dryness in vacuo to afford2-methoxybenzaldehyde oxime as an off white solid (1.1 g,) which wasused in Part 2 without further purification. ¹HNMR (400 MHz, DMSO-d₆)2.50 (s, 3H), 3.82 (s, 3H), 6.95 (t, 1H), 7.06 (d, 1H), 7.37 (t, 1H),7.65 (d, 1H), 8.28 (s, 1H), 11.20 (s, 1H).

Step 2: To a stirred solution of 2-methoxybenzaldehyde oxime (Step 1,500 mg, 3.311 mmols) in DMF (5 mL) was added NCS (530 mg, 3.974 mmol)and stirred at rt for 2 hrs. The reaction was diluted with water andextracted with MTBE (2×). The combined extracts were washed with water,brine, dried (Na₂SO₄) and evaporated to dryness in vacuo to afford(Z)—N-hydroxy-2-methoxybenzimidoyl chloride (400 mg, 65.08%) as an offwhite solid which was used without further purification.

Step 3: Et₃N (0.51 mL, 3.696 mmol) was added to a stirred solution of(Z)—N-hydroxy-2-methoxybenzimidoyl chloride (300 mg, 21.17 mmol) intoluene (7 mL) and methylpropargyl alcohol (167 mg, 2.39 mmol) intoluene (3 mL) at 0° C. The reaction mixture was heated to 80° C. for 3hrs. The reaction was filtered and filtrate concentrated under reducedpressure and the residue purified by combi flash using 10-20% EtOAc inhexane to afford the title compound as a light brown liquid (325 mg,68.19%). ¹HNMR (400 MHz, DMSO-d₆) 1.44 (d, 3H), 3.87 (d, 3H), 4.89 (m,1H), 5.75 (m, 1H), 6.67-6.74 (m, 1H), 7.01-7.25 (m, 2H), 7.45-7.54 (m,1H), 7.71-7.75 (m, 1H).

Preparation 126: 5-(1-chloroethyl)-3-(3-methoxyphenyl)isoxazole

The title compound was prepared in an analogous way to Preparation 124,from 1-(3-(3-methoxyphenyl)isoxazol-5-yl)ethan-1-ol (Preparation 127).¹HNMR (400 MHz, DMSO-de) 1.88 (d, 3H), 3.81 (s, 3H), 5.57 (m, 1H), 7.08(m, 1H), 7.25 (s, 1H), 7.38-7.48 (m, 3H).

Preparation 127: 1-(3-(3-methoxyphenyl)isoxazol-5-yl)ethan-1-ol

The title compound was prepared as a pale yellow solid in 44% yield (210mg), in an analogous way to Preparation 124 starting with3-methoxybenzaldehyde. ¹HNMR (400 MHz, DMSO-d₆) 1.45 (d, 3H), 3.81 (s,3H), 4.88 (m, 1H), 5.78 (d, 1H), 7.06 (m, 1H), 7.38-7.47 (m, 3H). LCMSm/z=220.4 [MH]⁺

Preparation 128: 5-(1-chloroethyl)-3-(2-fluorophenyl)isoxazole

SOCl₂ (1.225 mL, 16.891 mmol) was added to a stirred solution of1-(3-(2-fluorophenyl)isoxazol-5-yl)ethan-1-ol (Preparation 129, 1.0 g,4.826 mmol) in DCM at 0-5° C. The reaction was heated under reflux for 5hr, evaporated to dryness in vacuo and the residue diluted with EtOAc,washed with water, brine, dried (Na₂SO₄), and evaporated to dryness invacuo. The residue was purified by column chromatography on silica geleluting with 13% EtOAc/Hexane to afford the title compound as a brownliquid (600 mg, 55%). ¹HNMR (400 MHz, DMSO-d₆) 1.89 (d, 3H), 5.61 (q,1H), 7.04 (s, 1H), 7.32-7.46 (m, 2H), 7.58 (m, 1H), 7.90 (m, 1H). LCMSm/z=225 [M]⁺

Preparation 129: 1-(3-(2-fluorophenyl)isoxazol-5-yl)ethan-1-ol

Et₃N (38.202 mL, 274.225 mmol) was added to a stirred solution of2-fluoro-N-hydroxybenzimidoyl chloride (Preparation 130, 28 g, 161.3mmol) and but-3-yn-2-ol (13.53 mL, 177.4 mmol) in toluene at 0-5° C. Thereaction was stirred at 60° C. for 4 hr whereby it was cooled and thesolids removed by filtration. The filtrate was concentrated underreduced pressure. The resulting residue was purified by columnchromatography using 15% EtOAc/Hexane to afford the title compound as abrown liquid (15 g. 45%). ¹HNMR (400 MHz, DMSO-d₆) 1.46 (d, 3H), 4.92(m, 1H), 5.83 (d, 1H), 6.73 (d, 1H), 7.32-7.42 (m, 2H), 7.58 (m, 1H),7.89 (m, 1H). LCMS m/z=208.2 [MH]⁺

Preparation 130: 2-fluoro-N-hydroxybenzimidoyl chloride

NCS (26.39 g, 197.66 mmol) was added portion wise to a stirred solutionof (E)-2-fluorobenzaldehyde oxime (Preparation 131, 25.0 g, 179.69 mmol)in DMF (50 mL) at 10-20° C. The reaction mixture was stirred at rt for 4hrs, diluted with water and extracted with Et₂O. The combined organicextracts were washed with water, then brine, dried (Na₂SO₄) andevaporated to dryness in vacuo to afford the title compound (28 g, 90%)as a white gummy liquid. ¹HNMR (400 MHz, DMSO-d₆) 7.32 (m, 2H), 7.54 (m,1H), 7.64 (m, 1H), 12.61 (s, 1H).

Preparation 131: (E)-2-fluorobenzaldehyde oxime

To a suspension of 2-fluorobenzaldehyde (48 g, 386.75 mmol) andhydroxylamine hydrochloride (29.56 g, 425.42 mmol) in EtOH was addedwater below 10° C. An aqueous solution of NaOH was added drop wise at10° C. and the reaction stirred at rt for 12 hr. The reaction wasacidified to pH 4 with HCl (5N) and extracted with DCM. The combinedorganics were washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel using 4% EtOAc/Hexane to afford the title compound as a whitesolid (32 g, 59.47%). ¹HNMR (400 MHz, DMSO-d₆) 7.21-7.28 (m, 2H), 7.44(m, 1H), 7.74 (m, 1H), 8.23 (s, 1H). LCMS m/z=139 [M]⁺

Preparation 132: 5-(1-chloroethyl)-3-(o-tolyl)isoxazole

To a stirred solution of 1-[3-(o-tolyl)isoxazol-5-yl]ethan-1-ol(Preparation 133, 100 mg, 0.49 mmol) in DCM (5 mL) was added SOCl₂ (0.1mL, 1.476 mmol) and the reaction mixture was heated at reflux for 6 hr.The cooled reaction mixture was concentrated under reduced pressure andco-evaporated with DCM to afford the title compound (104 mg, crude) as abrown oil. ¹HNMR (400 MHz, DMSO-d₆) 1.88 (d, 3H), 2.43 (s, 3H), 5.59 (q,1H), 7.02 (s, 1H), 7.30-7.43 (m, 3H), 7.55 (d, 1H). LCMS m/z=222.0 [MH]⁺

Preparation 133: 1-[3-(o-tolyl)isoxazol-5-yl]ethan-1-ol

To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride(400 mg, 2.358 mmol) in toluene (10 mL) was added but-3-yn-2-ol (181 mg,2.594 mmol) followed by Et₃N (0.55 mL, 4.01 mmol) and the reactionstirred at 80° C. for 3 hrs. The cooled reaction mixture was filteredand the filtrate concentrated under reduced pressure to afford a brownliquid. This was purified by column chromatography on silica gel toafford the title compound (250 mg, 52.16%) as a light yellow liquid.¹HNMR (400 MHz, DMSO-d₆) 2.43 (s, 3H), 2.50 (s, 3H), 4.90 (m, 1H), 5.77(d, 1H), 6.67 (s, 1H), 7.29-7.40 (m, 3H), 7.51 (d, 1H). LCMS m/z=204.2[MH]⁺

Preparation 134: 5-(1-chloroethyl)-3-(3-fluorophenyl)isoxazole

To a stirred solution of 1-[3-(3-fluorophenyl)isoxazol-5-yl]ethanol (100mg, 0.483 mmols) in DCM (5 mL) was added SOCl₂ (0.12 mL, 1.69 mmol) andthe reaction stirred at reflux for 5 hr. The cooled reaction mixture wasconcentrated under reduced pressure; the resulting crude was trituratedwith hexane, filtered and dried under reduced pressure to afford thetitle compound (108 mg, quantitative) as a light yellow solid. ¹HNMR(400 MHz, CDCl₃) 1.93 (d, 3H), 5.15 (m, 1H), 6.57 (s, 1H), 7.13 (m, 1H),7.40-7.57 (m, 3H).

Preparation 135: 1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethan-1-ol

CH₃MgBr (90.2 mL, 126.32 mmol, 1.4 M) was added slowly to a stirredsolution of 2-(2-fluorophenyl)-1H-imidazole-5-carbaldehyde (Preparation136, 8 g, 42.105 mmol) in dry THF (250 mL) at 0° C. The resultingmixture was stirred for 30 mins at 0° C. followed by 3 hr at rt. Thereaction mixture was cooled to 0° C. and quenched with saturatedammonium chloride solution and extracted with EtOAc. The combinedorganics were washed with water, brine, dried (Na₂SO₄) and concentratedunder reduced pressure to afford the title compound as a pale yellowsolid (6.3 g, 72.6%). LCMS m/z=207.2 [MH]⁺

Preparation 136: 2-(2-fluorophenyl)-1H-imidazole-5-carbaldehyde

MnO₂ (45.28 g, 520.83 mmol) was added to a stirred solution of(2-(2-fluorophenyl)-1H-imidazol-5-yl)methanol (Preparation 110, 10 g,52.08 mmol) in DCM (320 mL) at 0° C. and the reaction mixture stirred atrt for 8 hrs. The reaction mixture was filtered through Celite® and thebed washed with DCM. The combined filtrate was evaporated to dryness invacuo and the residue purified by trituration with hexane to afford thetitle compound as an off white solid (7.8 g, 79%). ¹HNMR (400 MHz,DMSO-d₆) 7.36 (m, 2H), 7.52 (m, 1H), 8.00 (m, 1H), 8.13 (s, 1H), 9.80(s, 1H), 13.2 (brs, 1H). LCMS m/z=191 [MH]⁺

Preparation 137: 1-(2-(2,4-difluorophenyl)-1H-imidazol-4-yl)propan-1-ol

Step 1: To a 0° C. solution of LiHMDS (360 mL, 359.5 mmol) in THF (200mL) was added drop wise, 2,4-difluorobenzonitrile (20 g, 143.8 mmol) inTHF (100 mL). The reaction was warmed to rt and stirred for 4 hrs andc.HCl (100 mL) was added drop wise to keep the temperature below 30° C.EtOAc was added and the aqueous layer was collected. The pH was adjustedto 10 by the careful addition of 6N NaOH and the organic layercollected, dried and evaporated to dryness to give 2,4-difluorobenzimidamide (10 g, 44%) which was used without further purification inStep 2.

Step 2: To a solution of 2,4-difluorobenzimidamide (10 g, 64.0 mmol) inNH₃.H₂O (250 mL) was added 1,3-dihydroxypropan-2-one (11.5 g, 128.0mmol) and NH₄Cl (13.7 g). The reaction was stirred at 80° C. for 2 hrs,cooled, diluted with water extracted with EtOAc, dried and evaporated todryness. The residue was purified by column chromatography on silica gel(DCM/MeOH=9/1) to give (2-(2,4-difluorophenyl)-1H-imidazol-4-yl)methanol(2 g, 15%) which was used without further purification in Step 3.

Step 3: To a solution of(2-(2,4-difluorophenyl)-1H-imidazol-4-yl)methanol (Step 2, 2 g, 8.09mmol) in DCM (100 mL) was added MnO₂ (22.6 g, 66.6 mmol). The reactionwas stirred at rt for 4 hrs and the mixture filtered. The filtrate wascollected and evaporated in vacuo to give2-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (1.5 g, 75%) whichwas used without further purification in Step 4.

Step 4: To a solution of2-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (Step 3, 1.5 g, 7.2mmol) in THF (50 mL) was added EtMgBr (21.6 mL, 21.6 mmol) dropwise at0° C. After addition was complete the reaction was warmed to rt andstirred for 2 hrs. The reaction was quenched (c. NH₄Cl solution) andextracted with EtOAc. The combined extracts were washed (brine), driedand evaporated to give the title compound (1 g, 58%). LCMS m/z=239.2[MH]⁺

Preparation 138: Pent-1-yn-3-yl methansulfonate

Et₃N (745.6 mL, 5349.48 mmol) and DMAP (43.56 g, 356.61 mmol) were addedto an ice-cooled solution of pent-1-yn-3-ol (300 g, 3566.33 mmol) in DCM(2400 ml) and the solution stirred for 15 mins. Methane sulfonylchloride (333.48 ml, 4279.59 mmol) was added and the reaction stirred atrt for 3 hrs. The reaction mixture was quenched with water (1200 mL) at0° C. and organic layer was separated, washed with water (1200 mL),dried (Na₂SO₄) and concentrated in vacuo to afford the title compound asa brown liquid (580 gm, quant.). ¹HNMR (400 MHz, DMSO-d₆) 0.98 (t, 3H),1.82 (m, 2H), 3.23 (s, 3H), 3.86 (d, 1H), 5.21 (m, 1H).

Preparation 139:2-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

A mixture of 2-(difluoromethyl)-5-bromopyrimidine (500 mg, 2.23 mmol),bis(pinacolato)diboron (623 mg, 2.5 mmol) and KOAc (657 mg, 6.7 mmol) inDMF (11 mL) of DMF was degassed under N₂. Pd(dppf)Cl₂.DCM (82 mg, 0.11mmol) was added and the reaction stirred at 90° C. for 2.5 hrs. Thecooled reaction was poured into water and extracted with EtOAc (2×), thecombined organic extracts were washed with brine, dried (MgSO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography on silica gel eluting with EtOAc:Heptane (0:100 to20:80) to afford the title compound (388.8 mg, 68%). ¹HNMR (400 MHz,CDCl₃) 1.38 (s, 12H), 6.86-7.13 (dd, 1H), 8.52 (s, 2H). LCMS m/z=175.0[M-C₆H₁₀]⁺

Preparation 140:5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-5-fluoro-2-methoxypyridine (250 mg, 1.21 mmol) was added to astirred solution of KOAc (238.2 mg, 2.42 mmol) in dioxane (10 mL)followed by the addition of bispinacolatodiborane (308.1 mg, 1.21 mmol).The reaction mixture was degassed with N₂ for 10 mins andPdCl₂(dppf).DCM (99.02 mg, 0.12 mmol) added and degassed for another 10min. The reaction mixture was heated at 100° C. for 45 mins andevaporated to dryness under reduced pressure. The residue was dissolvedin 50% EtOAc in hexane, filtered through Celite® and evaporated todryness in vacuo afford the title compound (250 mg, 81.4%) which wasused without further purification. LCMS m/z=254 [MH]⁺

Preparation 141: 5-bromo-4-methoxy-2-(trifluoromethyl)pyrimidine

5-Bromo-4-chloro-2-(trifluoromethyl)pyrimidine (740 mg 2.83 mmol,) wasdissolved in MeOH (5.5 mL) and cooled in an ice/water bath. NaOMe (156mg 2.83 mmol) was dissolved in 2.5 mL of MeOH and added drop wise to thecooled solution. The reaction was allowed to warm to rt and stirredovernight. Additional NaOMe (60 mg) was added to the cooled reaction andstirred for another hour at rt. The reaction was quenched with water andextracted with DCM (2×). The combined organics were dried (MgSO₄), andevaporated to dryness to afford the title compound as an orange oil(638.7 mg, 98%) which was used without further purification. ¹HNMR (400MHz, CDCl₃) 4.08 (s, 3H), 8.62 (s, 1H).

Preparation 142: ethyl(Z)-2-amino-2-(2-(2-fluorobenzoyl)hydrazono)acetate

A solution of ethyl 2-ethoxy-2-iminoacetate (19 g, 123.26 mmol) and2-fluorobenzoic hydrazide (19.68 g, 135.59 mmol) in DCM (350 mL) wasstirred at reflux for 12 h. The resulting solid was collected byfiltration and washed with DCM (200 mL) to afford the title compound asan off-white solid (24.5 g, 80%). ¹HNMR (400 MHz, DMSO-d₆) 1.28 (t, 3H),4.25 (q, 2H), 6.66 (s, 2H), 7.29 (m, 2H), 7.57 (m, 2H), 10.18 (s, 1H).LCMS m/z=254 [MH]⁺

Preparation 143: Phenylazide

To a stirred solution of aniline (2 g, 21.475 mmol) in water (20 mL) wasadded HCl (10 mL) followed by a solution of NaNO₂ (1.92 g, 27.918 mmol)in water (10 mL) drop-wise at 0° C. The reaction mixture was stirred at0° C. for 30 min and to this was added solution of NaN₃ (1.67 g, 25.77mmol) in water (10 mL) at the same temperature and the resultingreaction mixture stirred at 0° C. for 1 h. The reaction mixture wasextracted with MTBE and the combined organics washed with water, NaHCO₃,brine, dried (Na₂SO₄) and concentrated under reduced pressure (keepingbath temperature at 10° C.) to afford the title compound as a yellowliquid (2.61 g) as yellow liquid. ¹HNMR (400 MHz, DMSO-d₆) 7.11 (d, 2H),7.19 (t, 1H), 7.42 (t, 2H).

Preparation 144: 2-Azido-3-fluoropyridine

To a stirred solution of 2-bromo-3-fluoro-pyridine (500 mg, 2.84 mmol)in EtOH:H₂O (20 mL) was added ethylenediamine (0.056 mL, 0.57 mmol),ascorbic acid (Na-salt) (112.6 mg, 0.57 mmol), CuI (54.11 mg, 0.3 mmol)and NaN₃ (277.0 mg, 4.3 mmol) at 0° C. and the reaction stirred at 80°C. for 16 hrs. The cooled mixture was concentrated in vacuo, the residuediluted with EtOAc, washed with water followed by brine and dried(Na₂SO₄). The organic layer was then filtered and evaporated underreduced pressure to afford the title compound as a yellow solid (300 mg,75.91%). ¹HNMR (400 MHz, DMSO-d₆) 7.47 (m, 1H), 7.81 (dd, 1H), 9.44 (d,1H). LCMS m/z=138 [MH]⁺, 110 [M-N₂]⁺

Preparation 145: 1-azido-2-fluorobenzene

A solution of NaNO₂ (6.52 g, 94.5 mmol) in H₂O (10 mL) was addeddropwise to a solution of 2-fluorobenzenamine (10 g, 90 mmol) in TFA (50mL) and H₂SO₄ (20 mL) while keeping internal temperature between 0-10°C. After addition was complete the mixture was kept at 0-10° C. for 1 hrand a solution of NaN₃ (6.44 g, 99 mmol) in H₂O (10 mL) added drop wisewhilst keeping the internal temperature between 0-10° C. and stirringfor a further hour. The reaction mixture was extracted with DCM (50 mL)and the combined extracts washed with sat aq. NaHCO₃ (20 mL×2), brine(20 mL) and dried (Na₂SO₄). The solvent was removed in vacuo to affordthe title compound (10 g, 81%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃)7.05-7.12 (m, 5H).

Preparation 146: 4-(1-chloroethyl)-1-(2,4-difluorophenyl)-1H-pyrazole

To a solution of 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethanol(Preparation 147, 6.0 g, 26.67 mmol) in DCM (15 mL) was added SOCl₂(4.83 mL, 66.67 mmol) at 0° C. under N₂ and the reaction stirred at rtfor 1 hr. The mixture was concentrated under reduced pressure to affordthe title compound as a brown oil (6.46 g, 99%). ¹HNMR (400 MHz, CDCl₃)1.90 (d, 3H), 5.21 (q, 1H), 7.01 (m, 2H), 7.78-7.85 (m, 2H), 7.93 (s,1H).

Preparation 147: 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethan-1-ol

To a solution of 1-(2,4-difluorophenyl)-1H-pyrazole-4-carbaldehyde (8 g,38.462 mmol) in THF (50 mL) was added CH₃MgBr (32 mL, 96.154 mmol) dropwise quickly at 0° C. After addition, the mixture was allowed to warm tort and stirred for another 30 min. The mixture was quenched with NH₄Clsolution then diluted with EtOAc (50 mL) and washed with brine (150mL×2). The organic solution was dried (Na₂SO₄) and concentrated to givethe desired product as an orange oil (6 g, 65%). ¹HNMR (400 MHz,DMSO-d₆) 1.38 (d, 3H), 4.77 (m, 1H), 5.08 (d, 1H), 7.24 (m, 1H), 7.52(m, 1H), 7.70 (s, 1H), 7.80 (m, 1H), 7.98 (d, 1H). LCMS m/z=225.1 [MH]⁺

Examples 1 and 2: 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers 1 and 2

To a solution of6-bromo-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 46, 160 mg, 0.30 mmol) in NMP (5 mL) was added Zn(CN)₂ (106 mg,0.91 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol) and dppf (33 mg, 0.06 mmol) andthe reaction stirred at 155° C. for 3 hrs under microwave irradiation.The cooled reaction was diluted with water and the mixture extractedwith EtOAc (30 mL×2). The organic layer was collected, washed withbrine, dried and evaporated under reduced pressure. The crude waspurified by column chromatography on silica gel eluting with pet. Ether:EtOAc (20:80) to afford4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile(80 mg, 56%). The product was further purified by prep HPLC method E6 toafford Example 1, enantiomer 1. ¹HNMR (400 MHz, DMSO-d₆): 2.01 (d, 3H),6.36 (m, 1H), 7.00-7.25 (br s, 2H), 7.10 (t, 1H), 7.33 (m, 1H), 7.42 (m,2H), 7.74 (t, 2H), 8.25 (d, 1H), 8.38 (s, 1H), 9.09 (s, 2H). LCMSm/z=476.2 [MH]⁺; RT [HPLC Method E7]=9.845 min.

Further elution provided Example 2, enantiomer 2. ¹HNMR (400 MHz,DMSO-d₆): 2.01 (d, 3H), 6.36 (m, 1H), 7.00-7.25 (brs, 2H), 7.10 (t, 1H),7.33 (m, 1H), 7.42 (m, 2H), 7.74 (t, 2H), 8.25 (d, 1H), 8.38 (s, 1H),9.09 (s, 2H). LCMS m/z=476.2 [MH]⁺; RT [HPLC Method E7]=10.941 min.

Examples 3 and 4:4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile, enantiomers1 and 2

4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile was preparedin 66% yield from6-bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 50),following the procedure described in Example 1/2. This was furtherpurified by prep HPLC method H3 to afford Example 3, enantiomer 1. ¹HNMR(400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.50 (d, 2H), 6.10 (t, 1H), 7.19 (brs, 2H), 7.30-7.48 (m, 3H), 7.75-7.80 (m, 2H), 8.26 (s, 1H), 8.39 (s,1H), 9.21 (s, 2H). LCMS m/z=508.2 [MH]⁺; RT [HPLC method C16]=4.128 min.

Further elution provided Example 4, enantiomer 2. ¹HNMR (400 MHz,DMSO-d₆): 0.86 (t, 3H), 2.53 (m, 2H), 6.10 (m, 1H), 7.18 (brs, 2H),7.35-7.46 (m, 3H), 7.74-7.79 (m, 2H), 8.26 (s, 1H), 8.39 (s, 1H), 9.21(s, 2H). LCMS m/z=508.1 [MH]⁺; RT [HPLC method C16]=7.540 min.

Examples 5 to 19

The following examples were obtained from the appropriate racemiccompound using appropriate chiral HPLC or SFC conditions.

Ex. Separation Method No. Structure Starting Material Analytical Data  5

HPLC Method C34; 4-Amino-7-(1-(1-(2- fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoro methyl) pyrimidin-5-yl)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (Example 31). ¹HNMR (400 MHz, DMSO-d₆) 2.01(d, 3H), 6.38 (q, 1H), 7.00-7.25 (br s, 2H), 7.33 (m, 1H), 7.44 (m, 2H),7.74 (m, 2H), 8.26 (s, 1H), 8.39 (s, 1H), 9.19 (s, 2H). LCMS m/z = 494.2[MH]⁺; RT [HPLC Method C11] = 4.324 min. enantiomer 1  6

HPLC Method C34; 4- Amino-7-(1-(1-(2-fluoro phenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoro methyl) pyrimidin-5-yl)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (Example 31). ¹HNMR (400 MHz, DMSO-d₆) 2.01(d, 3H), 6.38 (q, 1H), 7.00-7.25 (br s, 2H), 7.33 (m, 1H), 7.44 (m, 2H),7.74 (m, 2H), 8.26 (s, 1H), 8.39 (s, 1H), 9.19 (s, 2H). LCMS m/z = 494.2[MH]⁺; RT [HPLC Method C11] = 7.111 min. enantiomer 2  7

HPLC Method C25B; 4- Amino-7-{1-[1-(2,4- difluoro phenyl)-1H-pyrazol-4-yl]ethyl}-5-[2- (trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 32) ¹HNMR(400 MHz, DMSO-d₆) 2.00 (d, 3H), 6.37 (q, 1H), 7.00-7.25 (br s, 2H),7.25 (m, 1H), 7.57 (m, 1H), 7.70-7.80 (m, 2H), 8.23 (s, 1H), 8.39 (s,1H), 9.19 (s, 2H). LCMS m/z = 512.2 [MH]⁺; RT [HPLC Method C8] = 2.672min. enantiomer 1  8

HPLC Method C25B; 4- Amino-7-{1-[1-(2,4- difluoro phenyl)-1H-pyrazol-4-yl]ethyl}-5-[2- (trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 32) ¹HNMR(400 MHz, DMSO-d₆) 2.00 (d, 3H), 6.37 (q, 1H), 7.00-7.25 (br s, 2H),7.25 (m, 1H), 7.57 (m, 1H), 7.70-7.80 (m, 2H), 8.24 (s, 1H), 8.39 (s,1H), 9.19 (s, 2H). LCMS m/z = 512.2 [MH]⁺; RT [HPLC Method C8] = 3.283min. enantiomer 2  9

HPLC Method C23A; 4- amino-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- (trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 28) ¹HNMR(400 MHz, DMSO-d₆): 2.06 (d, 3H), 6.53 (q, 1H), 7.20 (br s, 2H), 7.43(m, 1H), 7.55- 7.63 (m, 2H), 7.79 (m, 1H), 8.38 (s, 1H), 8.79 (s, 1H),9.20 (s, 1H). LCMS m/z = 495.1 [MH]⁺; RT [HPLC Method C6] = 2.270 min.enantiomer 1 10

HPLC Method C23A; 4- Amino-7-{1-[1-(2-fluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine- 6-carbonitrile (Example 28) ¹HNMR (400 MHz,DMSO-d₆): 2.06 (d, 3H), 6.52 (q, 1H), 7.21 (br s, 2H), 7.43 (m, 1H),7.55- 7.63 (m, 2H), 7.77 (m, 1H), 8.38 (s, 1H), 8.79 (s, 1H), 9.20 (s,1H). LCMS m/z = 495.1 [MH]⁺; RT [HPLC Method C6] = 4.536 min. enantiomer2 11

HPLC Method C21; 4- Amino-7-{1-[1-(2,4- difluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- (trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 33) ¹HNMR(400 MHz, DMSO-d₆): 2.07 (d, 3H), 6.53 (q, 1H), 7.25-7.38 (m, 3H), 7.68(m, 1H), 7.83 (m, 1H), 8.40 (s, 1H), 8.78 (s, 1H), 9.20 (s, 2H). LCMSm/z = 513.1 [MH]⁺; RT [HPLC Method C5] = 2.393 min enantiomer 1 12

HPLC Method C32 4-amino-7-(1-(1-(2- fluorophenyl)-5-methyl-1H-1,2,3-triazol-4- yl)ethyl)-5-(2- (trifluoromethyl) pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidine-6-carbonitrile (Example 34) ¹HNMR(400 MHz, DMSO-d₆): 2.07 (s, 3H), 2.12 (d, 3H), 6.58 (m, 1H), 7.18 (brs, 2H), 7.45 (m, 1H), 7.55 (m, 2H), 7.67 (m, 1H), 8.40 (s, 1H), 9.20 (s,2H). LCMS m/z = 509.2 [MH]⁺; RT [HPLC Method C16A] = 5.733 minenantiomer 1 13

HPLC Method C32 4-amino-7-(1-(1-(2- fluorophenyl)-5-methyl-1H-1,2,3-triazol-4- yl)ethyl)-5-(2- (trifluoromethyl) pyrimidin-5-yl)-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 34) ¹HNMR(400 MHz, DMSO-d₆): 2.06 (s, 3H), 2.12 (d, 3H), 6.58 (m, 1H), 7.19 (brs, 2H), 7.47 (m, 1H), 7.59 (m, 2H), 7.67 (m, 1H), 8.40 (s, 1H), 9.20 (s,2H). LCMS m/z = 509.2 [MH]⁺; RT [HPLC Method C16A] = 6.505 minenantiomer 2 14

HPLC Method F7 4-amino-7-{1-[3-(2- fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxy pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile (Example 39) ¹HNMR (400 MHz, MeOD-d₄) 2.18 (d, 3H), 4.12(s, 3H), 6.58 (m, 1H), 6.99 (s, 1H), 7.27 (m, 2H), 7.55 (br s, 1H), 7.92(m, 1H), 8.36 (s, 1H), 8.78 (s, 2H). LCMS m/z = 457.2 [MH]⁺; RT [HPLCMethod F4] = 9.189 min enantiomer 1 15

HPLC Method F7 4-amino-7-{1-[3-(2- fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxy pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile (Example 39) ¹HNMR (400 MHz, MeOD-d₄) 2.18 (d, 3H), 4.11(s, 3H), 6.58 (m, 1H), 6.99 (s, 1H), 7.26 (m, 2H), 7.51 (br s, 1H), 7.92(m, 1H), 8.35 (s, 1H), 8.78 (s, 2H). LCMS m/z = 457.2 [MH]⁺; RT [HPLCMethod F4] = 13.190 min enantiomer 2 16

HPLC Method H1 4-Amino-7-{1-[1-(2,4- difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidin-6-carbonitrile (Example 38) ¹HNMR (400MHz, CDCl₃) 1.04 (t, 3H), 2.60-2.65 (m, 1H), 2.67- 2.76 (m, 1H), 5.36(br s, 2H), 6.40 (t, 1H), 7.06 (m, 2H), 7.91 (m, 1H), 8.25 (s, 1H), 8.49(s, 1H), 9.15 (s, 2H). LCMS m/z = 527.1 [MH]⁺; RT [HPLC Method H2] =3.613 min enantiomer 1 17

HPLC Method H1; 4-Amino-7-{1-[1-(2,4- difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidin-6-carbonitrile (Example 38) ¹HNMR (400MHz, CDCl₃) 1.04 (t, 3H), 2.60-2.65 (m, 1H) 2.67- 2.76 (m, 1H), 5.36 (brs, 2H), 6.40 (t, 1H), 7.06 (m, 2H), 7.87 (m, 1H), 8.25 (s, 1H), 8.49 (s,1H), 9.15 (s, 2H). LCMS m/z = 527.1 [MH]⁺; RT [HPLC Method H2] = 5.132min enantiomer 2 18

HPLC Method C21; 4-amino-7-{1-[1-(2,3- difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 36) ¹HNMR(400 MHz, DMSO-d₆) 0.92 (t, 3H), 2.56-2.62 (m, 2H) 6.29 (t, 1H), 7.20(br s, 2H), 7.45 (m, 1H) 7.67 (m, 2H), 8.38 (s, 1H), 8.83 (s, 1H), 9.22(s, 2H). LCMS m/z = 527.0 [MH]⁺; RT [HPLC Method C9] = 2.133 minenantiomer 1 19

HPLC Method C21; 4-amino-7-{1-[1-(2,3- difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (Example 36) ¹HNMR(400 MHz, DMSO-d₆) 0.92 (t, 3H), 2.56-2.62 (m, 2H) 6.30 (t, 1H), 7.20(br s, 2H), 7.45 (m, 1H) 7.67 (m, 2H), 8.38 (s, 1H), 8.83 (s, 1H), 9.22(s, 2H). LCMS m/z = 527.0 [MH]⁺; RT [HPLC Method C9] = 2.558 minenantiomer 2

Examples 20 and 21:4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,enantiomers 1 and

A mixture of6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 51, 150 mg, 0.25 mmol) in NMP (2 mL) was added Zn(CN)₂ (59 mg,0.5 mmol), dppf (14 mg, 0.025 mmol) and Pd₂(dba)₃ (23 mg, 0.025 mmol)under N₂ and the reaction heated under microwave irradiation for 1.5 hrsat 155° C. The cooled mixture was diluted with water (25 mL) and themixture extracted with DCM (15 mL×4). The combined organic layer wasdried (Na₂SO₄), filtered and the filtrate was evaporated under reducedpressure. The residue was purified by prep-HPLC eluting with MeCN inwater (0.1% TFA) from 55% to 65% to give4-amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile(90 mg, 68%) as a yellow solid. This solid was further purified bychiral HPLC Method E8, to afford Example 20, enantiomer 1. ¹HNMR (400MHz, DMSO-d₆): 0.86 (t, 3H), 2.53 (m, 2H), 6.10 (m, 1H), 7.17 (brs, 2H),7.24 (t, 1H), 7.53 (t, 1H), 7.76 (m, 2H), 8.24 (s, 1H), 8.38 (s, 1H),9.21 (s, 2H). LCMS m/z=526.2 [MH]⁺; RT [HPLC method C17]=3.301 min.

Further elution provided Example 21, enantiomer 2. ¹HNMR (400 MHz,DMSO-d₆): 0.86 (t, 3H), 2.53 (m, 2H), 6.10 (m, 1H), 7.17 (brs, 2H), 7.24(t, 1H), 7.53 (t, 1H), 7.76 (m, 2H), 8.24 (s, 1H), 8.38 (s, 1H), 9.21(s, 2H). LCMS m/z=526.2 [MH]⁺; RT [HPLC method C17]=7.568 min.

Example 22 and 23:4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers1 and 2

To a solution of6-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 52, 3.3 g, 6.238 mmol) in DMF (30 mL) was added Zn(CN)₂ (1.04g, 8.82 mmol), dppf (0.65 g, 1.176 mmol) and Pd₂(dba)₃ (0.57 g, 0.624mmol) and the reaction stirred in a microwave reactor at 140° C. for 2hr under N₂. The cooled mixture was concentrated and diluted with EtOAc(150 mL). The organic solution was washed with brine (2×100 ml), dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified byprep-HPLC to give4-amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile(1.7 g, 56%) as a white solid. The compound was further purified bychiral HPLC Method C20B to afford, Example 23, enantiomer 1. ¹HNMR (400MHz, DMSO-d₆): 0.92 (t, 3H), 2.57-2.62 (m, 2H), 6.30 (t, 1H), 7.20 (brs,2H), 7.42 (m, 1H), 7.52-7.60 (m, 2H), 7.80 (m, 1H), 8.38 (s, 1H), 8.78(s, 1H), 9.22 (s, 2H). LCMS m/z=509.2 [MH]⁺; RT [HPLC Method C5]=2.143min.

Further elution provided Example 23, enantiomer 2. ¹HNMR (400 MHz,DMSO-d₆): 0.92 (t, 3H), 2.57-2.62 (m, 2H), 6.30 (t, 1H), 7.22 (brs, 2H),7.42 (m, 1H), 7.52-7.60 (m, 2H), 7.80 (m, 1H), 8.38 (s, 1H), 8.78 (s,1H), 9.22 (s, 2H). LCMS m/z=509.2 [MH]⁺; RT [HPLC Method C5]=2.585 min.

Example 24:4-Amino-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,single enantiomer

Copper cyanide (32 mg, 0.35 mmol) was added to a solution of6-bromo-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,single enantiomer (Example 55, 66 mg, 0.12 mmol) in DMF (1 mL) thereaction degassed with N₂ and heated at 165° C. for 1 hr under microwaveirradiation. The cooled reaction was diluted with DCM (30 mL), 30% NH₄OHadded and the mixture stirred vigorously for 45 min. The phases wereseparated, the aqueous extracted with DCM and the combined organicextracts washed with 30% NH₄OH (30 mL), then dried (MgSO₄), filtered,and concentrated in vacuo. The orange oil was suspended in DCM/heptaneand evaporated under reduced pressure to provide an orange solid. Thiswas purified by HPLC to yield the title compound (27 mg, 44%). ¹HNMR(400 MHz, DMSO-d₆): 0.92 (t, 3H), 2.56-2.62 (m, 2H), 6.25 (m, 1H), 7.26(m, 2H), 7.42-7.47 (m, 1H), 7.55-7.65 (m, 2H), 7.80 (m, 1H), 8.18 (m,1H), 8.34 (s, 1H), 8.42 (s, 1H), 8.75 (s, 1H). LCMS m/z=506.3 [MH]⁺

Example 25:4-Amino-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

To a solution of6-bromo-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 43, 0.15 g, 0.34 mmol) in DMF (3 mL) was added Zn(CN)₂ (40 mg,0.50 mmol), Pd₂(dba)₃ (31 mg, 0.034 mmol) and dppf (38 mg, 0.068 mmol)and the reaction stirred at 140° C. for 3 hrs. The cooled mixture wasdiluted with water then extracted with EtOAc, the organic phase washedwith brine, dried and evaporated. The crude product was purified byprep-HPLC to give the title compound (25.6 mg, 19%). ¹HNMR (400 MHz,DMSO-d₆): 1.35 (d, 6H), 4.46 (m, 1H), 5.34 (s, 2H), 7.42 (s, 1H), 7.54(d, 2H), 7.62 (d, 2H), 7.76 (s, 1H), 8.35 (s, 1H). LCMS m/z=392.2 [MH]⁺

Example 26:4-Amino-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

A mixture of6-bromo-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 56, 20 mg, 0.04 mmol), Zn(CN)₂ (4.71 mg, 0.04 mmol), Pd₂(dba)₃(1.84 mg, 0.002 mmol) and TFP (1.40 mg, 0.006 mmol) in DMF (0.4 mL) in amicrowave vial was purged under Ar. The reaction was then heated at 90°C. for 18 hrs under microwave irradiation. The cooled mixture wasfiltered through Celite® and the filtrate purified by columnchromatography on silica gel eluting with MeOH:DCM (0:100 to 5:95) toafford the title compound (4.6 mg, 26%). ¹HNMR (400 MHz, CDCl₃): 5.10(s, 2H), 5.45 (br s, 2H), 7.28-7.58 (m, 7H), 7.92 (m, 1H), 8.28 (s, 1H),8.50 (s, 1H). LCMS m/z=445.1[MH]⁺

Example 27:4-Amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

A mixture of6-bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 40, 1.5 g, 2.81 mmol), Zn(CN)₂ (660 mg, 5.63 mmol), Pd₂(dba)₃(258 mg, 0.281 mmol), dppf (306 mg, 0.563 mmol) and DMF (15 mL) wasstirred at 140° C. for 1 hr under N₂ under microwave irradiation. Thecooled mixture was concentrated under reduced pressure to give a residuewhich was purified by silica gel column (eluting with DCM:MeOH=10:1) toafford the title compound (500 mg, yield: 37.1%) as a brown solid. ¹HNMR(400 MHz, DMSO-d₆): 5.54 (s, 2H), 7.18 (brs, 2H), 7.32-7.47 (m, 3H),7.76 (m, 1H), 7.79 (s, 1H), 8.26 (d, 1H), 8.41 (s, 1H), 9.21 (s, 2H).LCMS m/z=480.0 [MH]⁺

The solid material was further purified by silica gel column (elutingwith 50-100% EtOAc/CH₂Cl₂ gradient) to provide the desired product as alight yellow solid which was slurried in ethanol. The slurry was chilledfor 1 hour and collected by vacuum filtration, washing with minimalchilled ethanol. The title compound was obtained as a crystalline solid(415 mg, 30.8%) after drying under high vacuum overnight. ¹HNMR (400MHz, DMSO-d₆): 5.55 (s, 2H), 7.19 (brs, 2H), 7.34-7.38 (m, 1H),7.41-7.50 (m, 2H), 7.78 (m, 1H), 7.80 (s, 1H), 8.27 (s, 1H), 8.43 (s,1H), 9.22 (s, 2H). LCMS m/z=480.0 [MH]⁺

Example 28:4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile

To a solution of6-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 44, 0.2 g, 0.36 mmol) in DMF (6 mL) was added Zn(CN)₂ (64 mg,0.55 mmol), Pd₂(dba)₃ (33 mg, 0.036 mmol) and dppf (40 mg, 0.072 mmol)under N₂ and the reaction stirred at 140° C. for 1.5 hr under microwaveirradiation. The cooled mixture was partitioned between water and EtOAc,the layers separated and the organic phase washed with brine, dried andevaporated under reduced pressure. The crude product was purified byprep-HPLC to afford the title compound (110 mg, 61.8%). LCMS m/z=495.1[MH]⁺

Examples 29 to 36

The following examples were prepared according to an analogous procedureto that described in Example 28, from the appropriate bromo startingmaterial.

Ex. No. Structure Starting Material Analytical Data 29^(a)

6-Bromo-7-{[1-(2,4- difluorophenyl)-1H- pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl) pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 41) ¹HNMR (400 MHz, DMSO-d₆): 5.53 (s, 2H), 7.00-7.30 (m, 3H),7.53 (t, 1H), 7.70-7.85 (m, 2H), 8.23 (s, 1H), 8.41 (s, 1H), 9.21 (s,2H). LCMS m/z = 498.2 [MH]⁺ 30^(a)

6-Bromo-5-[2-(difluoro methyl)pyrimidin-5-yl]-7- {[1-(2-fluorophenyl)-1H- pyrazol-4-yl]methyl}-7H- pyrrolo [2,3-d]pyrimidin-4- amine(Example 42) ¹HNMR (400 MHz, DMSO-d₆) 5.52 (s, 2H), 6.94-7.50 (m, 6H),7.74- 7.78 (m, 2H), 8.25 (s, 1H), 8.40 (s, 1H), 9.11 (s, 2H). LCMS m/z =462.2 [MH]⁺ 31

6-Bromo-7-{1-[1-(2- fluorophenyl)-1H-pyrazol- 4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 47) LCMS m/z = 512.2 [MH]⁺ 32

6-Bromo-7-{1-[1-(2,4- difluorophenyl)-1H- pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 48) LCMS m/z = 512.0 [MH]⁺ 33

6-Bromo-7-{1-[1-(2,4- difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example 45) ¹HNMR (400 MHz,DMSO-d₆) 2.06 (d, 3H), 6.53 (q, 1H), 7.32-7.40 (m, 3H), 7.69 (m, 1H),7.84 (m, 1H), 8.41 (s, 1H), 8.79 (s, 1H), 9.21 (s, 2H). LCMS m/z = 513.1[MH]⁺ 34

6-Bromo-7-{1-[1-(2- fluorophenyl)-5-methyl- 1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 49) LCMS m/z = 509.1 [MH]⁺ 35

6-Bromo-7-{1-[1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3-d] pyrimidin-4-amine(Example 52) ¹HNMR (400 MHz, MeOD-d₄): 0.93 (t, 3H), 2.60 (m, 2H), 6.31(m, 1H), 7.30-7.65 (m, 5H), 7.80 (m, 1H), 8.42 (s, 1H), 8.80 (s, 1H),9.24 (s, 2H). LCMS m/z = 509.1 [MH]⁺ 36^(a)

6-Bromo-7-{1-[1-(2,3- difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example 54) LCMS m/z = 527.0[MH]⁺ ^(a)NMP was used as the reaction solvent, instead of DMF.

Example 37:4-Amino-7-{[1-(2-difluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile

Step 1: To a solution ofN′-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 60, 500 mg, 1.02 mmol) in dioxane (10 mL) was added H₂O (2mL), 2-(trifluoromethyl) pyrimidin-5-ylboronic acid (391 mg, 2.04 mmol),PdCl₂(dppf) (75 mg, 0.102 mmol) and K₂CO₃ (282 mg, 2.04 mmol) and thereaction stirred at 100° C. for 5 hr under N₂. The cooled mixture wasfiltered and the filtrate concentrated. The residue was diluted withEtOAc (150 mL) the solution washed with brine (2×150 mL), dried (Na₂SO₄)and concentrated. The crude product was purified by columnchromatography on silica gel eluting with MeOH:DCM (1:20) to giveN′-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamideas a yellow solid (300 mg, 57%). LCMS m/z=511.2 [MH]⁺

Step 2: To a solution ofN′-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Step 1, 300 mg, 0.588 mmol) in MeOH (5 mL) was added NH₃.H₂O (5 mL) andthe reaction stirred at 70° C. for 18 hrs in a sealed tube. The cooledmixture was concentrated to give a brown solid (240 mg, 90%).

Step 3: To an ice-cooled solution of the solid from Step 2, in DMF (4mL) was added NBS (103 mg, 0.578 mmol) portion wise over 1 min and themixture then allowed to warm to rt and stirred for 18 hrs. The mixturewas concentrated in vacuo and the crude product was purified by columnchromatography on silica gel eluting with MeOH:DCM (1:20) to give thetitle compound as a yellow solid (140 mg, 50%).

LCMS m/z=511.2 [MH]⁺

Step 4: To a solution of the compound from Step 3, (140 mg, 0.262 mmol)in DMF (4 mL) was added CuCN (71 mg, 0.787 mmol) in a microwave vial.The solution was degassed with N₂ for 2 min, then the reaction heated at160° C. for 2 hr under microwave irradiation. The cooled reaction wasfiltered and concentrated in vacuo. The crude product was purified byprep-HPLC to afford the title compound as a white solid (9.4 mg, 7%).¹HNMR (400 MHz, MeOD-d₄): 5.83 (s, 2H), 7.33-7.49 (m, 2H), 7.52-7.62 (m,1H), 7.82 (m, 1H), 8.38 (s, 1H), 8.51 (d, 1H), 9.19 (s, 2H). LCMSm/z=481.1 [MH]⁺

Example 38:4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile

A solution of6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 53, 170 mg, 0.29 mmol), Zn(CN)₂ (137 mg, 1.17 mmol), Pd₂(dba)₃(40 mg, 0.044 mmol) and dppf (48 mg, 0.087 mmol) in DMF (3 mL) wasstirred at 145° C. for 2 hr under microwave irradiation. The cooledmixture was evaporated under reduced pressure to give a residue whichwas purified by column chromatography on silica gel eluting withMeOH:DCM (0:100 to 10:90) to afford the desired compound as a brownsolid (80 mg, 52.44%). LCMS m/z=527.0 [MH]⁺

Example 39:4-Amino-7-{(1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Step 1: To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(Preparation 71, 1.2 g, 4.285 mmol) in DMF (8 mL) was added 18-Crown-6(1.13 g, 4.285 mmol), K2CO₃ (1.18 g, 8.571 mmol) and5-(1-chloroethyl)-3-(2-fluorophenyl)isoxazole (Preparation 128, 1.34 g,4.714 mmol). The mixture was stirred at 60° C. for 2 hr, evaporated todryness in vacuo, diluted with EtOAc (80 mL) and washed with brine(2×100 mL), dried (Na₂SO₄) and concentrated. The residue was purified ona 20 g silica column eluting with MeOH:DCM (1:30) to give5-[1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)-3-(2-fluorophenyl)isoxazole (1.42 g, 71%)as an orange solid. LCMS m/z=468.9 [MH]⁺

Step 2: To a solution of the compound from Step 1, (1.42 g, 3.04 mmol)in dioxane (15 mL) was added NH₃.H₂O (5 mL). The mixture was stirred at90° C. overnight in a sealed tube and then evaporated to dryness to give1-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-3-iodo-1H-pyrrolo[2,3-d]pyridin-4-amineas a white solid (1.3 g, 97.0%) which was used in Step 3. LCMS m/z=450.0[MH]⁺

Step 3: To a solution of the compound from Step 2, (1.3 g, 2.895 mmol)in dioxane (16 mL) was added H₂O (4 mL), 2-methoxypyrimidin-5-ylboronicacid (0.54 g, 3.474 mmol), PdCl₂(pddf).DCM (0.21 g, 0.289 mmol) andK₂CO₃ (0.8 g, 5.790 mmol) and the mixture stirred at 90° C. for 3 hrunder N₂. The reaction mixture was filtered, and evaporated to drynessin vacuo. The residue was purified by column chromatography on silicagel eluting with MeOH:DCM (1:20) to give7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineas a brown solid (0.77 g, yield 61%) which was used in Step 4. LCMSm/z=432.1 [MH]⁺

Step 4: To a solution of the compound from Step 3, (0.77 g, 1.786 mmol)in DMF (15 mL) was added NBS (0.35 g, 1.965 mmol) portion wise. Themixture was stirred at 0° C. overnight, concentrated and diluted withEtOAc (80 mL). The organic layer was washed with brine (2×70 mL), dried(Na₂SO₄) and evaporated to dryness in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with MeOH:DCM (1:20) to give5-(4-amino-6-bromo-7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-2-olas a brown solid (0.56 g, 62%) which was used in Step 5. LCMS m/z=510.0,512.0 [MH]⁺

Step 5: To a solution of the compound from Step 4, (560 mg, 1.1 mmol) inDMF (15 mL) in a microwave vial was added Zn(CN)₂ (193 mg, 1.65 mmol),dppf (123 mg, 0.22 mmol) and Pd₂(dba)₃ (100 mg, 0.11 mmol). The mixturewas stirred in a microwave reactor at 140° C. for 2 hr under N₂atmosphere. The mixture was concentrated and diluted with EtOAc (100mL), washed with brine (2×100 mL), dried (Na₂SO₄) and concentrated. Theresidue was purified by prep-HPLC to give the title compound (92.9 mg,18%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): 2.06 (s, 3H), 4.00 (s,3H), 6.51 (m, 1H), 6.98-7.17 (m, 3H), 7.32-7.45 (m, 2H), 7.60 (m, 1H),7.89 (m, 1H), 8.34 (s, 1H), 8.74 (s, 2H). LCMS m/z=457.2 [MH]⁺

Example 40:6-Bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a mixture of7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 57, 13 g, 28.6 mmol) and DCM (130 mL) was added NBS (5.09 g,28.6 mmol) in several portions at 0° C. and the mixture stirred at 0° C.for 60 min. The reaction was quenched (5% NaHCO₃ solution), extractedwith DCM (150 mL×3), washed (brine, 100 mL×1), dried (Na₂SO₄) and thesolvent removed in vacuo. The residue was purified by silica gel column(eluting with DCM:MeOH=20:1) to afford the title compound (13 g, 86%) asa yellow solid. ¹HNMR (400 MHz, CDCl₃): 5.54 (s, 2H), 5.65 (brs, 2H),7.19-7.29 (m, 3H), 7.81-7.82 (m, 2H), 8.16 (m, 1H), 8.44 (s, 1H), 9.06(s, 2H). LCMS m/z=532.9 [MH]⁺

Examples 41 to 55

The following examples were prepared following an analogous procedure tothat described in Example 40, from the appropriatepyrrolo[2,3-d]pyrimidin-4-amine starting material.

Ex. No. Structure Starting Material Analytical Data 41

7-{[1-(2,4-Difluoro phenyl)-1H-pyrazol-4- yl]methyl}-5-(2-(trifluoromethyl) pyrimidin-5-yl)- 7H-pyrrolo[2,3-d] pyrimidin-4-amine (Example279) ¹HNMR (400 MHz, DMSO-d₆) 5.46 (s, 2H), 6.66 (br s, 2H), 7.23 (t,1H), 7.51 (t, 1H), 7.70- 7.85 (m, 2H), 8.18 (s, 1H), 8.27 (s, 1H), 9.06(s, 2H). LCMS m/z = 550.9 and 552.9 [MH]⁺ 42

5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol- 4-yl]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 204) ¹HNMR (400 MHz, DMSO-d₆) 5.46 (s, 2H), 6.61 (br s,2H), 7.05 (t, 1H), 7.30-7.50 (m, 3H), 7.75 (m, 2H), 8.34 (s, 2H), 8.98(s, 2H). LCMS m/z = 515.1 and 517.1 [MH]⁺ 43

5-(4-Chlorophenyl)-7-{[1- (propan-2-yl)-1H-pyrazol- 4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 254) LCMS m/z = 447.1 [MH]⁺ 44

7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4- yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 216) LCMS m/z = 548.1 and 550.0 [MH]⁺ 45

7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol- 4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 217) LCMS m/z = 566.0 and 568.0 [MH]⁺ 46

5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol- 4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 205) ¹HNMR (400 MHz, DMSO-d₆) 2.08 (d, 3H),6.26 (br s, 1H), 6.54 (br s, 2H), 7.10 (t, 1H), 7.25- 7.50 (m, 3H), 7.75(m, 2H), 8.20 (m, 2H), 8.98 (s, 2H). LCMS m/z = 529.1 and 531.1 [MH]⁺ 47

7-{1-[1-(2-Fluorophenyl)- 1H-pyrazol-4-yl]ethyl}-5- [2-(trifluoromethyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 277) LCMSm/z = 547.0 and 549.0 [MH]⁺ 48

7-{1-[1-(2,4-Difluoro phenyl)-1H-pyrazol-4- yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example275) LCMS m/z = 564.9 and 566.9 [MH]⁺ 49

7-{1-[1-(2-Fluorophenyl)- 5-methyl-1H-1,2,3-triazol- 4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 273) LCMS m/z 562.0 [MH⁺] 50

7-{1-[1-(2-Fluorophenyl)- 1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 271) LCMS m/z = 561.0 and 563.0 [MH]⁺ 51

7-{1-[1-(2,4-Difluoro phenyl)-1H-pyrazol-4- yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example274) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.48 (m, 2H), 5.98 (br s,1H), 7.23 (t, 1H), 7.25- 7.40 (br s, 2H), 7.58 (t, 1H), 7.70-7.80 (m,2H), 8.22 (s, 1H), 8.36 (s, 1H), 9.11 (s, 2H). LCMS m/z = 579.0 and581.1 [MH]⁺ 52

7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4- yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example224) ¹HNMR (400 MHz, CDCl₃) 1.03 (t, 3H), 2.65 (m, 2H), 5.19 (br s, 2H),6.27 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H), 7.95 (m, 1H), 8.05 (s, 1H),8.38 (s, 1H), 8.41(m, 1H), 9.11 (s, 2H). LCMS m/z = 562.0 [MH]⁺

Example 56:6-Bromo-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

CuI (19.6 mg, 0.102 mmol), Hunig's base (0.33 mL, 1.85 mmol) and2-fluorophenyl azide (35.6 mg, 0.259 mmol) were added to a suspension of6-bromo-5-(4-chlorophenyl)-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 76, 67 mg, 0.19 mmol) in t-BuOH (0.5 mL) and toluene (2 mL)and the reaction stirred at rt for 18 hrs. NH₄OH (20 mL) was added andthe mixture extracted with EtOAc (3×50 mL). The combined organicextracts were dried (Na₂SO₄), filtered and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel to afford the title compound (26 mg, 28%). ¹HNMR (400 MHz,CDCl₃): 5.20 (brs, 2H), 5.78 (s, 2H), 7.28-7.34 (m, 2H), 7.44-7.51 (m,5H), 7.94 (m, 1H), 8.13 (s, 1H), 8.36 (m, 1H). LCMS m/z=499.9 [MH]⁺

Example 57:7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 55, 17 g, 39.2 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(16 g, 58.8 mmol), Pd(dppf)Cl₂ (1.43 g, 1.96 mmol) and K₂CO₃ (13.5 g, 98mmol) in DMF (170 mL) and water (17 mL) was stirred at 85° C. for 6 hunder N₂. The resulting mixture was filtered and concentrated to give ablack solid which was purified by silica gel column eluting with pet.ether:EtOAc (2:1) to afford the title compound (13 g, 73%) as a paleyellow solid. ¹HNMR (400 MHz, CDCl₃): 5.25 (brs, 2H), 5.45 (s, 2H),7.20-7.30 (m, 3H), 7.76 (s, 1H), 7.86 (m, 1H), 8.00 (s, 1H), 8.10 (d,1H); 8.48 (s, 1H), 9.03 (s, 2H). LCMS m/z=455.1 [MH]⁺

Example 58:5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine(Preparation 77, 800 mg, 2.70 mmol) in toluene (24 mL) and tBuOH (8 mL)were added CuI (283 mg, 1.49 mmol), DIPEA (0.29 mL, 1.69 mmol) and themixture then cooled in ice. 1-Azido-2-fluorobenzene (676 mg, 4.87 mmol)was added and the reaction stirred for 16 hrs at rt. The mixture wasfiltered through Celite®, washing through with EtOAc and the filtrateconcentrated in vacuo. The solid was diluted with water, extracted withEtOAc, the combined organic extracts washed with water, then brine,dried (Na₂SO₄) and concentrated under reduced pressure. The crudecompound was purified by column chromatography on silica gel elutingwith EtOAc:Hexane (60:40) to afford the title compound, as a pale yellowsolid (550 mg, 46.9%). ¹HNMR (400 MHz, DMSO-d₆): 1.91 (d, 3H), 6.12-6.22(brs, 2H), 6.31 (m, 1H), 7.42-7.59 (m, 8H), 7.80 (m, 1H), 8.19 (s, 1H),8.66 (s, 1H). LCMS m/z=434.0 [MH]⁺

Examples 59 to 71

Examples 59-71 were prepared via a palladium catalysed boronic acidcross-coupling of7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 57) and 13 different boronic acids or esters using the ninestep reaction protocol described below.

-   -   1. A 0.3 M solution of boronic acid or ester monomers in        degassed mixture of Dioxane:EtOH:H₂O (7:3:2) was prepared        (solution B).    -   2. A 0.2 M solution of        7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine        (Preparation 57) in degassed mixture of Dioxane:EtOH:H₂O (7:3:2)        was prepared (solution A).    -   3. 10 mL 2M solution of Na₂CO₃ was prepared in degassed        distilled water (solution C).    -   4. 500 □L of solution A (1.5 eq, 150 nmol) was added followed by        500 □L of solution B (1 eq, 100 nmol) to each reaction vial        under argon purging condition.    -   5. 150 □L (3 eq, 300 nmol) of solution C was added to each vial.    -   6. Pd(PPh₃)₄ (0.1 eq, 10 nmol, 12 mg) was dispensed as solid        under argon flow.    -   7. Each reaction vial was stirred at 100° C. for 16 hrs.    -   8. Reactions were filtered and solvent was evaporated in thermo        explorer (1 hr, 5 torr, and 45° C.).    -   9. 1 mL DMSO was added to the crude products. 10 μL of the DMSO        solution was diluted to 200 μL with DMSO for QC analysis and        remaining amount was submitted for prep-HPLC to afford the title        compounds.

Ex. No. Structure Purification Method Analytical Data 59

HPLC Method N1 RT [HPLC Method M1] = 1.43 minutes LCMS m/z = 447.25[MH]⁺ 60

HPLC Method L2 RT [HPLC Method M1] = 1.29 minutes LCMS m/z = 389.25[MH]⁺ 61

HPLC Method P1 RT [HPLC Method M1] = 1.32 minutes LCMS m/z = 450.27[MH]⁺ 62

HPLC Method P1 RT [HPLC Method M1] = 1.35 minutes LCMS m/z = 439.29[MH]⁺ 63

HPLC Method P1 RT [HPLC Method M1] = 1.38 minutes LCMS m/z = 482.29[MH]⁺ 64

HPLC Method N1 RT [HPLC Method M1] = 1.44 minutes LCMS m/z = 468.27[MH]⁺ 65

HPLC Method N1 RT [HPLC Method M1] = 1.34 minutes LCMS m/z = 470.3 [MH]⁺66

HPLC Method L2 RT [HPLC Method M1] = 1.34 minutes LCMS m/z = 439.29[MH]⁺ 67

HPLC Method N1 RT [HPLC Method M1] = 1.36 minutes LCMS m/z = 444.32[MH]⁺ 68

HPLC Method P1 RT [HPLC Method M1] = 1.49 minutes LCMS m/z = 431.3 [MH]⁺69

HPLC Method L2 RT [HPLC Method M1] = 1.46 minutes LCMS m/z = 466.27[MH]⁺ 70

HPLC Method P1 RT [HPLC Method M1] = 1.46 minutes [MH]⁺ 71

HPLC Method L2 RT [HPLC M1] = 1.24 minutes LCMS m/z = 389.26 [MH]⁺

Examples 72 to 86

Examples 72 to 86 were prepared via a palladium catalysed boronic acidcross-coupling of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 41) and 15 different boronic acids or esters using theeight step reaction protocol described below.

-   -   1. A 0.2 M solution of boronic acid or ester monomers in        degassed mixture of DM F:H₂O (4:1) was prepared (solution A).    -   2. A 0.2 M solution of        7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine        (Preparation 41) in degassed mixture of DMF:H₂O (4:1) was        prepared (solution B).    -   3. 500 □L of solution A (1 eq, 100 □mol) was added followed by        500 □L of solution B (1 eq, 100 nmol) to each reaction vial        under argon purging condition. 4. 98 mg (3 eq, 300 nmol) of        anhydrous Cs₂CO₃ was added to each vial.    -   5. PdCl₂ (dppf).DCM (0.17 eq, 17 nmol, 15 mg) was dispensed        under argon flow.    -   6. Each reaction vial was stirred at 100° C. for 16 hrs.    -   7. Reactions were filtered and solvent was evaporated in thermo        explorer (1 hr, 5 t torr, 45° C.).    -   8. 1 mL DMSO was added to the crude products. 10 μL of the DMSO        solution was diluted to 200 μL with DMSO for QC analysis and        remaining amount was purified by prep-HPLC to afford the title        compounds.

Ex. No. Structure Purification Method Analytical Data 72

HPLC Method N2 RT [HPLC Method M1] = 1.48 min LCMS m/z = 441.3 [MH]⁺ 73

HPLC Method N2 RT [HPLC Method M1] = 1.45 min LCMS m/z = 440.32 [MH]⁺ 74

HPLC Method N2 RT [HPLC Method M1] = 1.46 min LCMS m/z = 428.27 [MH]⁺ 75

HPLC Method N2 RT [HPLC Method M1] = 1.52 min LCMS m/z = 448.27 [MH]⁺ 76

HPLC Method N2 RT [HPLC Method M1] = 1.41 min LCMS m/z = 440.32 [MH]⁺ 77

HPLC Method P1 RT [HPLC Method M1] = 1.53 min LCMS m/z = 442.27 [MH]⁺ 78

HPLC Method P1 RT [HPLC Method M1] = 1.44 minutes LCMS m/z = 440.28[MH]⁺ 79

HPLC Method P1 RT [HPLC Method M1] = 1.45 min LCMS m/z = 441.3 [MH]⁺ 80

HPLC Method N1 RT [HPLC Method M1] = 1.39 min LCMS m/z = 426.28 [MH]⁺ 81

HPLC Method N1 RT [HPLC Method M1] = 1.44 min LCMS m/z = 425.3 [MH]⁺ 82

HPLC Method N1 RT [HPLC Method M1] = 1.51 min LCMS m/z = 450.23 [MH]⁺ 83

HPLC Method N2 RT [HPLC Method M1] = 1.75 min LCMS m/z = 452.27 [MH]⁺ 84

HPLC Method N2 RT [HPLC Method M1] = 1.48 min LCMS m/z = 441.25 [MH]⁺ 85

HPLC Method N1 RT [HPLC Method M1] = 1.46 min LCMS m/z = 416.28 [MH]⁺ 86

HPLC Method N2 RT [HPLC Method M1] = 1.44 min LCMS m/z = 440.28 [MH]⁺

Examples 87 to 100

The following compounds of generic structure:

were prepared according to the following procedure.1. 0.2 M solution of appropriate boronic acid in a degassed mixture ofDMF:H₂O (4:1) was prepared (solution A).2. 0.2 M solution of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42) in degassed mixture of DMF:H₂O (4:1) was prepared(solution B).3. 500 μL of solution A (1 eq, 100 μmol) followed by 500 μL of solutionB (1 eq, 100 μmol) was added to each reaction vial under Ar.4. 98 mg (3 eq, 300 μmol) of anhydrous Cs₂CO₃ was added to each vial.5. PdCl₂ (dppf).DCM (0.17 eq, 17 μmol, 15 mg) was dispensed under Ar.6. Each reaction vial was stirred at 100° C. for 16 hrs.7. The reactions were filtered and solvent evaporated in vacuo.8. DMSO (1 mL) was added to the crude products and the solutionspurified by preparative HPLC to afford the desired compounds.

Example Structure of Purification Number Group W Method Analytical Data 87

HPLC Method L1 LCMS m/z = 460.22 [MH]⁺; RT [HPLC Method M1] = 1.47 min 88

HPLC Method K1 LCMS m/z = 446.31 [MH]⁺; RT [HPLC Method M1] = 1.56 min 89

HPLC Method K1 LCMS m/z = 466.27 [MH]⁺; RT [HPLC Method M1] = 1.55 min 90

HPLC Method L1 LCMS m/z = 464.18 [MH]⁺; RT [HPLC Method M1] = 1.57 min 91

HPLC Method L1 LCMS m/z = 448.18 [MH]⁺; RT [HPLC Method M1] = 1.51 min 92

HPLC Method L1 LCMS m/z = 454.23 [MH]⁺; RT [HPLC Method M1] = 1.47 min 93

HPLC Method L1 LCMS m/z = 484.26 [MH]⁺; RT [HPLC Method M1] = 1.61 min 94

HPLC Method J1 LCMS m/z = 400.29 [MH]⁺; RT [HPLC Method M1] = 1.49 min 95

HPLC Method L1 LCMS m/z = 454.36 [MH]⁺; RT [HPLC Method M1] = 1.46 min 96

HPLC Method K1 LCMS m/z = 442.24 [MH]⁺; RT [HPLC Method M1] = 1.48 min 97

HPLC Method K1 LCMS m/z = 468.18 [MH]⁺; RT [HPLC Method M1] = 1.61 min 98

HPLC Method K1 LCMS m/z = 452.15 [MH]⁺; RT [HPLC Method M1] = 1.61 min 99

HPLC Method J1 LCMS m/z = 452.24 [MH]⁺; RT [HPLC Method M1] = 1.62 min100

HPLC Method J1 LCMS m/z = 451.3 [MH]⁺; RT [HPLC Method M1] = 1.51 min^(a)Boronate ester used instead of boronic acid. The bond with the arrowindicates the point of attachment of Group W.

Examples 101 to 107

The following examples were prepared via a palladium catalysed boronicacid cross-coupling of7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 59) and 7 different boronic acids or boronate esters usingthe reaction protocol described below.

-   -   1. A 0.2 M solution of boronic acid or ester monomers in        degassed mixture of DMF:H₂O (4:1) was prepared (solution A).    -   2. A 0.2 M solution of        7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine        (Preparation 59) in degassed mixture of DMF:H₂O (4:1) was        prepared (solution B).    -   3. 500 □L of solution A (1 eq, 100 □mol) was added followed by        500 □L of solution B (1 eq, 100 nmol) to each reaction vial        under argon purging condition.    -   4. 98 mg (3 eq, 300 □mol) of anhydrous Cs₂CO₃ was added to each        vial.    -   5. PdCl₂ (dppf).DCM (0.17 eq, 17 □mol, ˜15 mg) was dispensed        under argon flow.    -   6. Each reaction vial was stirred at 100° C. for 16 hrs.    -   7. Reactions were filtered and solvent was evaporated in thermo        explorer (1 h, 5 t torr, 45° C.).    -   8. 1 mL DMSO was added to the crude products. 10 μL of the DMSO        solution was diluted to 200 μL with DMSO for QC analysis and        remaining amount was purified by prep-HPLC to afford the title        compounds.

Ex. No. Structure Purification Method Analytical Data 101

HPLC Method L2 RT [HPLC Method M1] = 1.52 min LCMS m/z = 469.22 [MH]⁺102

HPLC Method K1 RT [HPLC Method M1] = 1.58 min LCMS m/z = 458.2 [MH]⁺ 103

HPLC Method L2 RT [HPLC Method M1] = 1.49 min LCMS m/z = 440.28 [MH]⁺104

HPLC Method K1 RT [HPLC Method M1] = 1.65 min LCMS m/z = 442.18 [MH]⁺105

HPLC Method K1 RT [HPLC Method M1] = 1.6 min LCMS m/z = 443.2 [MH]⁺ 106

HPLC Method K1 RT [HPLC Method M1] = 1.49 min LCMS m/z = 457.12 [MH]⁺107

HPLC Method L2 RT [HPLC Method M1] = 1.68 min LCMS m/z = 484.13 [MH]⁺

Examples 108 to 182

The following examples were obtained from the appropriate racemiccompound using the chiral HPLC or SFC conditions described.

Ex. Separation Method No. Structure Starting Material Analytical Data108

SFC Method A7; 5-Cyclopropyl-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 238)¹HNMR (400 MHz, DMSO-d₆) 0.52-0.58 (m, 2H), 0.84-0.89 (m, 2H), 1.82 (d,3H), 2.04 (m, 1H), 6.18 (m, 1H), 6.58 (br s, 2H), 6.97 (d, 1H), 7.44 (m,1H), 7.55-7.62 (m, 2H), 7.82 (m, 1H), 8.16 (s, 1H), 8.55 (s, 1H). LCMSm/z = 364.4 [MH]⁺; RT [SFC Method A8] = 4.338 min Enantiomer 1 109

SFC Method A7; 5-cyclopropyl-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 238)¹HNMR (400 MHz, DMSO-d₆) 0.52-0.58 (m, 2H), 0.84-0.89 (m, 2H), 1.82 (d,3H), 2.04 (m, 1H), 6.18 (m, 1H), 6.58 (br s, 2H), 6.97 (d, 1H), 7.44 (m,1H), 7.55-7.62 (m, 2H), 7.82 (m, 1H), 8.16 (s, 1H), 8.55 (s, 1H). LCMSm/z = 364.4 [MH]⁺; RT [SFC Method A8] = 4.645 min Enantiomer 2 110

SFC Method A9; 5-Cyclobutyl-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 247)¹HNMR (400 MHz, DMSO-d₆) 1.91-1.95 (m, 1H), 2.00-2.20 (m, 8H), 2.33-2.42(m, 2H), 5.07 (s, 2H), 6.31 (m, 1H), 7.23-7.31 (m, 2H), 7.41 (m, 1H),7.92 (m, 2H), 8.26 (s, 1H). LCMS m/z = 378.2 [MH]⁺; RT [SFC Method A8] =5.199 min Enantiomer 2 111

SFC Method A1; 5-(4-Chlorophenyl)-7-{1- [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- 7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example58) ¹HNMR (400 MHz, CDCl₃) 2.12 (d, 3H), 5.48 (br s, 2H), 6.48 (m, 1H),7.35-7.60 (m, 8H), 7.98 (m, 1H), 8.10 (s, 1H), 8.38 (s, 1H). LCMS m/z =434.1 [MH]⁺; [α]_(D) MeOH = −51.12°; RT [SFC Method A2] = 6.350 minEnantiomer 1 112

SFC Method A1; 5-(4-Chlorophenyl)-7-{1- [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- 7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example58) ¹HNMR (400 MHz, CDCl₃) 2.12 (d, 3H), 5.49 (m, 2H), 6.45 (m, 1H),7.32-7.60 (m, 8H), 7.98 (m, 1H), 8.10 (s, 1H), 8.38 (m, 1H). LCMS m/z =434.1 [MH]⁺; [α]_(D) MeOH = +48.3°; RT [SFC Method A2] = 6.884 minEnantiomer 2 113

SFC Method B1; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]ethyl}-5-(2-methoxy pyridin-3-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine(Example 215) ¹HNMR (400 MHz, DMSO-d₆) 1.90 (d, 3H), 3.86 (s, 3H), 6.04(br s, 2H), 6.31 (m, 1H), 7.06 (m, 1H), 7.42 (m, 2H), 7.53-7.65 (m, 3H)7.82 (m, 1H), 8.17 (m, 2H), 8.65 (s, 1H). LCMS m/z = 431.2 [MH]⁺;[α]_(D) MeOH = −27.9°; RT [SFC Method B2] = 5.598 min Enantiomer 1 114

SFC Method B1; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]ethyl}-5-(2-methoxy pyridin-3-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine(Example 215) ¹HNMR (400 MHz, DMSO-d₆) 1.90 (d, 3H), 3.86 (s, 3H), 6.04(br s, 2H), 6.31 (m, 1H), 7.06 (m, 1H) 7.42 (m, 2H), 7.53-7.65 (m, 3H),7.82 (m, 1H), 8.17 (m, 2H), 8.65 (s, 1H). LCMS m/z = 431.2 [MH]⁺;[α]_(D) MeOH = +32.6°; RT [SFC Method B2] = 5.775 min Enantiomer 2 115

SFC Method A1; 4-(4-Amino-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorobenzonitrile (Example 239) ¹HNMR (400 MHz, DMSO-d₆) 1.95 (d,3H), 6.34 (m, 1H), 6.48 (br s, 2H), 7.44 (m, 2H), 7.48 (m, 2H) 7.52-7.60(m, 2H), 7.82 (m, 1H), 7.96 (m, 1H), 8.25 (s, 1H), 8.68 (s, 1H). LCMSm/z = 443.0 [MH]⁺; RT [SFC Method A2] = 6.451 min Enantiomer 1 116

SFC Method A1; 4-(4-Amino-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorobenzonitrile (Example 239) ¹HNMR (400 MHz, DMSO-d₆) 1.95 (d,3H), 6.34 (m, 1H), 6.48 (br s, 2H), 7.44 (m, 2H), 7.48 (m, 2H) 7.52-7.60(m, 2H), 7.82 (m, 1H), 7.96 (m, 1H), 8.25 (s, 1H), 8.68 (s, 1H). LCMSm/z = 443.0 [MH]⁺; RT [SFC Method A2] = 7.408 min Enantiomer 2 117

SFC Method C1 5-[4-(Cyclopropyloxy) phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 212) ¹HNMR (400 MHz, DMSO-d₆): 0.68(m, 2H), 0.78 (m, 2H), 1.90 (d, 3H), 3.87 (m, 1H), 6.32 (q, 1H), 7.14(m, 2H), 7.37-7.44 (m, 4H) 7.55- 7.61 (m, 2H), 7.81 (m, 1H), 8.18 (s,1H), 8.65 (s, 1H) LCMS m/z = 456.5 [MH]⁺; [α]_(D) MeOH = +48.8°; RT [SFCMethod C2] = 6.871 min Enantiomer 1 118

SFC Method C1 5-[4-(Cyclopropyloxy) phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 212) ¹HNMR (400 MHz, DMSO-d₆): 0.68(m, 2H), 0.78 (m, 2H), 1.90 (d, 3H), 3.87 (m, 1H), 6.32 (q, 1H), 7.14(m, 2H), 7.37-7.44 (m 4H) 7.55- 7.61 (m, 2H), 7.81 (m, 1H), 8.18 (s,1H), 8.65 (s, 1H) LCMS m/z = 456.5 [MH]⁺; [α]_(D) MeOH = −42.9°; RT[SFC- method C2] = 7.555 min Enantiomer 2 119

SFC Method A3; 5-[4-(Cyclopropyloxy) pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 213) ¹HNMR (400 MHz, DMSO-d₆)0.69 (m, 2H), 0.78 (m, 2H), 1.91 (d, 3H), 4.22 (m, 1H), 6.18 (br s, 2H),6.32 (q, 1H), 6.93 (d, 1H), 7.43 (m, 1H), 7.47 (s, 1H), 7.53- 7.61 (m,2H), 7.77-7.84 (m, 2H), 8.18 (s, 1H), 8.26 (d, 1H), 8.65 (s, 1H). LCMSm/z = 457.1 [MH]⁺; [α]_(D) MeOH = −48.8°; RT [SFC Method A5] = 5.808 minEnantiomer 1 120

SFC Method A3; 5-[4-(Cyclopropyloxy) pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 213) ¹HNMR (400 MHz, DMSO-d₆)0.69 (m, 2H), 0.78 (m, 2H), 1.91 (d, 3H), 4.22 (m, 1H), 6.18 (br s, 2H),6.32 (q, 1H), 6.93 (d, 1H), 7.43 (m, 1H), 7.47 (s, 1H), 7.53- 7.61 (m,2H), 7.77-7.84 (m, 2H), 8.18 (s, 1H), 8.26 (d, 1H), 8.65 (s, 1H). LCMSm/z = 457.1 [MH]⁺; [α]_(D) MeOH = +50.1°; RT [SFC Method A5] = 6.269 minEnantiomer 2 121

HPLC Method F1; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]ethyl}-5-(1H-pyrazol-3-yl)- 7H-pyrrolo[2,3-d] pyrimidin-4-amine (Example218) ¹HNMR (400 MHz, MeOD-d₄) 1.96 (d, 3H), 6.30 (m, 1H), 6.59 (m, 1H),7.28-7.33 (m, 2H), 7.46 (m, 1H), 7.67 (s, 1H), 7.74 (m, 1H), 7.82 (s,1H), 8.12 (s, 1H), 8.37 (s, 1H). LCMS m/z = 390.1 [MH]⁺; RT [HPLC MethodF3] = 6.657 min Enantiomer 1 122

HPLC Method F1; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]ethyl}-5-(1H-pyrazol-3-yl)- 7H-pyrrolo[2,3-d] pyrimidin-4-amine (Example218) ¹HNMR (400 MHz, MeOD-d₄) 1.96 (d, 3H), 6.30 (m, 1H), 6.59 (m, 1H),7.28-7.33 (m, 2H), 7.46 (m, 1H), 7.67 (s, 1H), 7.74 (m, 1H), 7.82 (s,1H), 8.12 (s, 1H), 8.37 (s, 1H). LCMS m/z = 390.1 [MH]⁺; RT [HPLC MethodF3] = 11.212 min Enantiomer 2 123

HPLC method C20B; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoro methyl) pyrimidin-5-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 217) ¹HNMR (400 MHz, DMSO-d₆) 1.97 (d, 3H),6.37 (q, 1H) 7.33 (m 1H), 7.54-7.70 (m, 3H), 7.87 (m, 1H), 8.00 (s, 1H),8.42 (s, 1H), 8.69 (s, 1H), 9.09 (s, 2H). LCMS m/z = 488.1 [MH]⁺; RT[HPLC Method C5] = 2.711 min Enantiomer 1 124

HPLC method C20B; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoro methyl) pyrimidin-5-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 217) ¹HNMR (400 MHz, DMSO-d₆) 1.97 (d, 3H),6.36 (q, 1H) 7.33-7.45 (m, 3H), 7.67 (m, 1H), 7.87 (m, 1H), 8.00 (s,1H), 8.40 (s, 1H), 8.69 (s, 1H), 9.08 (s, 2H). LCMS m/z = 488.1 [MH]⁺;RT [HPLC Method C5] = 3.982 min Enantiomer 2 125

HPLC method B4; 5-(6-methoxypyridin-3-yl)- 7-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example 220)¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.35 (m, 2H), 3.15 (s, 3H), 6.06(t, 1H), 6.18 (br s, 2H), 6.90 (d, 1H), 7.49 (m, 2H), 7.60 (m, 2H), 7.78(m, 1H), 7.89 (m, 2H), 8.19 (s, 1H), 8.25 (s, 1H), 8.93 (s, 1H). LCMSm/z = 427.2 [MH]⁺; RT [HPLC Method B2] = 4.530 min Enantiomer 1 126

HPLC method B4; 5-(6-methoxypyridin-3-yl)- 7-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example 220)¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.35 (m, 2H), 3.15 (s, 3H), 6.08(t, 1H), 6.18 (br s, 2H), 6.90 (d, 1H), 7.49 (m, 2H), 7.60 (m, 2H), 7.78(m, 1H), 7.89 (m, 2H), 8.19 (s, 1H), 8.25 (s, 1H), 8.93 (s, 1H). LCMSm/z = 427.2 [MH]⁺; RT [HPLC Method B2] = 9.460 min Enantiomer 2 127

SFC Method C4; 5-(4-Methoxypyrimidin-5- yl)-7-{1-[1-phenyl-1H-1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example248) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H), 2.38 (m, 2H), 3.94 (s, 3H),6.18 (m, 1H), 6.30 (s, 2H), 7.50 (m, 2H), 7.60 (m, 2H), 7.88 (m, 2H),8.18 (s, 1H), 8.42 (s, 1H), 8.70 (s, 1H), 8.94 (s, 1H). LCMS m/z = 428.3[MH]⁺; [α]_(D) MeOH = −21.8°; RT [SFC Method C2] = 6.113 min Enantiomer1 128

SFC Method C4; 5-(4-Methoxypyrimidin-5- yl)-7-{1-[1-phenyl-1H-1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3- d]pyrimidin-4-amine (Example248) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H), 2.38 (m, 2H), 3.96 (s, 3H),6.10 (m, 1H), 6.30 (s, 2H), 7.50 (m, 2H), 7.60 (m, 2H), 7.88 (m, 2H),8.18 (s, 1H), 8.42 (s, 1H), 8.70 (s, 1H), 8.94 (s, 1H). LCMS m/z = 428.3[MH]⁺; [α]_(D) MeOH = +23.6°; RT [SFC Method C2] = 6.382 min Enantiomer2 129

HPLC Method B4; 7-[1-(1-phenyl-1H-1,2,3- triazol-4-yl)propyl]-5-[2-(trifluromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 219) ¹HNMR (400 MHz, DMSO-d₆): 0.87 (t, 3H), 2.34-2.44 (m, 2H),6.12 (t, 1H), 7.60 (m, 2H), 7.89 (m, 3H), 8.34 (s, 1H), 8.95 (s, 1H),9.08 (s, 2H). LCMS m/z = 466.1 [MH]⁺; RT [HPLC Method E2] = 10.002 minEnantiomer 1 130

HPLC Method B4; 7-[1-(1-phenyl-1H-1,2,3- triazol-4-yl)propyl]-5-[2-(trifluromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 219) ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.33-2.43 (m, 2H),6.11 (m, 1H), 6.18 (br s, 2H), (t, 1H), 6.80 (s, 2H), 7.49 (m, 1H), 7.59(m, 2H), 7.88 (m, 3H), 8.29 (m, 1H), 8.94 (s, 1H), 9.07 (s, 2H). LCMSm/z = 466.1 [MH]⁺; RT [HPLC Method E2] = 12.342 min Enantiomer 2 131

SFC Method A7; 5-(4-Chlorophenyl)-7-{1- [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3-d] pyrimidin-4-amine (Example211) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.38 (m, 2H), 6.12 (m, 1H),6.18 (br s, 2H), 7.42 (m, 1H), 7.48-7.63 (m, 7H), 7.83 (m, 1H), 8.18 (s,1H), 8.72 (s, 1H). LCMS m/z = 448.2 [MH]⁺; RT [SFC Method A8] = 6.274min Enantiomer 1 132

SFC Method A7; 5-(4-Chlorophenyl)-7-{1- [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3-d] pyrimidin-4-amine (Example211) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.38 (m, 2H), 6.12 (m, 1H),6.18 (br s, 2H), 7.42 (m, 1H), 7.48-7.63 (m, 7H), 7.83 (m, 1H), 8.18 (s,1H), 8.72 (s, 1H). LCMS m/z = 448.2 [MH]⁺; [α]_(D) MeOH = +53.2°; RT[SFC Method A8] = 7.088 min Enantiomer 2 133

SFC Method B4, 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxy pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 244) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.35 (m, 2H),3.94 (s, 3H), 6.12 (t, 1H), 6.32 (br s, 2H), 7.42 (m, 1H), 7.53-7.62 (m,2H), 7.82 (m, 2H), 8.18 (d, 1H), 8.42 (s, 1H), 8.72 (d, 1H), 8.76 (s,1H). LCMS m/z = 446.2 [MH]⁺; [α]D MeOH = −18.2°; RT [SFC Method B2] =5.194 min Enantiomer 1 134

SFC Method B4; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxy pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 244) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.35 (m, 2H),3.94 (s, 3H), 6.12 (t, 1H), 6.32 (br s, 2H), 7.42 (m, 1H), 7.53-7.62 (m,2H), 7.82 (m, 2H), 8.18 (s, 1H), 8.42 (s, 1H), 8.72 (d, 1H), 8.76 (s,1H). LCMS m/z = 446.2 [MH]⁺; [α]D MeOH = +20.6°; RT [SFC Method B2] =5.597 min Enantiomer 2 135

SFC Method D1; 7- {1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxy pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 251) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t,3H), 2.48 (m, 2H), 3.90 (s, 3H), 6.25 (m, 1H), 7.45 (m, 1H), 7.52-7.62(m, 2H), 7.84 (m, 1H), 8.22- 8.30 (m, 3H), 8.78 (s, 1H), 8.82 (d, 1H).LCMS m/z = 446.2 [MH]⁺; [α]D MeOH = −98.9°, RT [SFC Method D2] = 8.390minutes Enantiomer 1 136

SFC Method D1; 7- {1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxy pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 251) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t,3H), 2.48 (m, 2H), 3.90 (s, 3H), 6.25 (m, 1H), 7.45 (m, 1H), 7.52-7.62(m, 2H), 7.84 (m, 1H), 8.22- 8.30 (m, 3H), 8.78 (s, 1H), 8.82 (d, 1H).LCMS m/z = 446.2 [MH]⁺; [α]_(D) MeOH = +87.6°; RT [SFC Method D2] =9.059 mins Enantiomer 2 137

SFC Method C29; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[2-[2 methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d] pyrimidin-4-amine (Example 224) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H), 2.39 (m, 2H),6.13 (m, 1H), 6.66 (br s, 2H), 7.43 (m, 1H), 7.52-7.70 (m, 2H), 7.80 (m,1H), 7.95 (s, 1H), 8.25 (s, 1H), 8.72 (s, 1H), 9.06 (s, 2H). LCMS m/z =484.2 [MH]⁺; RT [HPLC Method C6] = 3.893 min Enantiomer 1 138

SFC Method C29; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 224) ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H),2.39 (m, 2H), 6.13 (m, 1H), 6.66 (br s, 2H), 7.43 (m, 1H), 7.52-7.70 (m,2H), 7.80 (m, 1H), 7.95 (s, 1H), 8.25 (s, 1H), 8.72 (s, 1H), 9.06 (s,2H). LCMS m/z = 484.2 [MH]⁺; RT [HPLC Method C6] = 5.176 min Enantiomer2 139

SFC Method C5; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 223) ¹HNMR (400 MHz, DMSO-d₆)0.86 (t, 3H), 2.39 (m, 2H), 3.86 (s, 3H), 6.09 (m, 1H), 6.24 (br s, 2H),7.45 (m, 1H), 7.57-7.65 (m, 4H), 7.85 (m, 1H), 8.12 (d, 1H), 8.18 (s,1H), 8.72 (s, 1H). LCMS m/z = 463.1 [MH]⁺; [α]_(D) MeOH = +37.1°; RT[SFC Method C2] = 2.90 min Enantiomer 1 140

SFC Method C5; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 223) ¹HNMR (400 MHz, DMSO-d₆)0.86 (t, 3H), 2.39 (m, 2H), 3.86 (s, 3H), 6.09 (m, 1H), 6.24 (br s, 2H),7.45 (m, 1H), 7.57-7.65 (m, 4H), 7.85 (m, 1H), 8.12 (d, 1H), 8.18 (s,1H), 8.72 (s, 1H). LCMS m/z = 463.1 [MH]⁺; [α]_(D) MeOH = −33.7°; RT[SFC Method C2] = 3.19 min Enantiomer 2 141

SFC Method B4; 5-[6-(Difluoromethoxy) pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 240) ¹HNMR (400 MHz, DMSO-d₆)0.86 (t, 3H), 2.39 (m, 2H), 6.10 (m, 1H), 7.17 (d, 1H), 7.43 (m, 1H),7.52-7.62 (m, 2H), 7.74 (s, 1H), 7.82 (m, 1H), 7.89 (s, 1H), 7.95 (d,1H), 8.25 (s, 1H), 8.33 (s, 1H), 8.72 (s, 1H). LCMS m/z = 481.3 [MH]⁺;[α]_(D) MeOH = −31.7°; RT [SFC Method B2] = 6.160 min Enantiomer 1 142

SFC Method B4; 5-[6-(Difluoromethoxy) pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 240) ¹HNMR (400 MHz, DMSO-d₆)0.86 (t, 3H), 2.39 (m, 2H), 6.10 (m, 1H), 7.17 (d, 1H), 7.43 (m, 1H),7.52-7.62 (m, 2H), 7.74 (s, 1H), 7.82 (m, 1H), 7.89 (s, 1H), 7.95 (d,1H), 8.25 (s, 1H), 8.33 (s, 1H), 8.72 (s, 1H). LCMS m/z = 481.3 [MH]⁺;[α]_(D) MeOH = +37.1°; RT [SFC Method B2] = 7.065 min Enantiomer 2 143

HPLC Method C22A; 5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 221) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H),2.39 (m, 2H), 6.12 (m, 1H), 6.60 (br s, 2H), 6.88-7.14 (dd, 1H), 7.41(m, 1H), 7.52-7.62 (m, 2H), 7.82-7.80 (m, 2H), 8.24 (s, 1H), 8.71 (s,1H), 9.00 (s, 2H). LCMS m/z = 466.1 [MH]⁺; RT [HPLC Method C7] = 2.873min Enantiomer 1 144

HPLC Method C22A; 5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 221) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H),2.39 (m, 2H), 6.12 (m, 1H), 6.60 (br s, 2H), 6.88-7.14 (dd, 1H), 7.41(m, 1H), 7.52-7.62 (m, 2H), 7.82-7.80 (m, 2H), 8.24 (s, 1H), 8.71 (s,1H), 9.00 (s, 2H). LCMS m/z = 466.1 [MH]⁺; RT [HPLC Method C7] = 3.931min Enantiomer 2 145

HPLC Method C24A; 5-[2-(Dimethylamino) pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 222) ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.33 (m, 2H) 3.16 (s, 6H), 6.08 (m, 1H), 6.24 (br s, 2H),7.41 (m, 1H), 7.53 (s, 1H) 7.56-7.63 (m, 2H), 7.84 (m, 1H), 8.17 (s,1H), 8.41 (s, 2H), 8.69 (s, 1H). LCMS m/z = 459.2 [MH]⁺; RT [HPLC MethodA] = 1.278 min Enantiomer 1 146

HPLC Method C24A; 5-[2-(Dimethylamino) pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 222) ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.33 (m, 2H) 3.16 (s, 6H), 6.08 (m, 1H), 6.24 (br s, 2H),7.41 (m, 1H), 7.53 (s, 1H) 7.56-7.63 (m, 2H), 7.84 (m, 1H), 8.17 (s,1H), 8.41 (s, 2H), 8.69 (s, 1H). LCMS m/z = 459.2 [MH]⁺; RT [HPLC MethodA] = 1.278 min Enantiomer 2 147

HPLC Method F2; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(1H-pyrazol- 3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 226) ¹HNMR (400 MHz, MeOD-d₄) 0.96 (t, 3H), 2.43-2.51 (m, 2H),6.09 (m, 1H), 6.64 (s, 1H), 7.35-7.45 (m, 2H), 7.56 (m, 1H), 7.66 (s,1H), 7.76 (s, 1H), 7.85 (m, 1H), 8.12 (s, 1H), 8.43 (s, 1H). LCMS m/z =404.1 [MH]⁺; RT [HPLC Method D3] = 4.538 min Enantiomer 1 148

HPLC Method F2; 7-{1-[1-(2-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-(1H-pyrazol- 3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine(Example 226) ¹HNMR (400 MHz, MeOD-d₄) 0.96 (t, 3H), 2.43-2.51 (m, 2H),6.09 (m, 1H), 6.65 (s, 1H), 7.35-7.45 (m, 2H), 7.56 (m, 1H), 7.66 (s,1H), 7.76 (s, 1H), 7.83 (m, 1H), 8.13 (s, 1H), 8.43 (s, 1H). LCMS m/z =404.1 [MH]⁺; RT [HPLC Method D3] = 5.961 min Enantiomer 2 149

SFC Method A4; 7-{1-[1-(4-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxy pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 241) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H),3.92 (s, 3H), 6.08 (m, 1H), 6.29 (br s, 2H), 7.42-7.48 (m, 3H), 7.95 (m,2H), 8.16 (s, 1H), 8.41 (s, 1H), 8.69 (s, 1H), 8.92 (s, 1H). LCMS m/z =446.01 [MH]⁺; [α]_(D) MeOH = +24.1°; RT [SFC Method A5] = 6.959 minEnantiomer 1 150

SFC Method A4; 7-{1-[1-(4-Fluorophenyl)- 1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxy pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 241) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H),3.92 (s, 3H), 6.08 (m, 1H), 6.32 (br s, 2H), 7.42-7.50 (m, 3H), 7.95 (m,2H), 8.18 (s, 1H), 8.41 (s, 1H), 8.69 (s, 1H), 8.92 (s, 1H). LCMS m/z =446.01 [MH]⁺; [α]_(D) MeOH = −23.8°; RT [SFC Method A5] = 7.770 minEnantiomer 2 151

SFC Method A3; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- methoxypyrimidin-5-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 245) ¹HNMR (400 MHz, DMSO-d₆): 0.84 (t, 3H),2.33 (m, 2H), 3.92 (s, 3H), 6.08 (m, 1H), 6.32 (br s, 2H), 7.35 (m, 1H),7.54 (s, 1H), 7.72 (m, 1H), 7.90 (m, 1H), 8.18 (m, 1H), 8.42 (s, 1H),8.70 (s, 1H), 8.77 (s, 1H). LCMS m/z = 465.3 [MH]⁺; [α]_(D) MeOH =+28.5° Enantiomer 1 152

SFC Method A3; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- methoxypyrimidin-5-yl] 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 245) ¹HNMR (400 MHz, DMSO-d₆): 0.84 (t, 3H),2.33 (m, 2H), 3.92 (s, 3H), 6.08 (m, 1H), 6.32 (br s, 2H), 7.35 (m, 1H),7.54 (s, 1H), 7.72 (m, 1H), 7.90 (m, 1H), 8.18 (m, 1H), 8.42 (s, 1H),8.70 (s, 1H), 8.77 (s, 1H). LCMS m/z = 465.3 [MH]⁺; [α]_(D) MeOH =−22.5° Enantiomer 2 153

HPLC Method G2; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 227) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H),2.31-2.43 (m, 2H), 6.10 (t, 1H), 6.70 (s, 2H), 7.72 (m, 2H), 7.82 (m,1H), 8.08 (m, 1H), 8.26 (s, 1H), 8.94 (s, 1H), 9.06 (s, 2H). LCMS m/z =502.2 [MH]⁺; RT [HPLC Method G1] = 6.820 min Enantiomer 1 154

HPLC Method G2; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 227) ¹HNMR (400 MHz, DMSO-d₆) 0.87 (t, 3H),2.34-2.43 (m, 2H), 6.12 (t, 1H), 7.27 (s, 2H), 7.68 (m, 2H), 7.75 (m,1H), 7.93 (s, 1H), 8.37 (s, 1H), 8.96 (s, 1H), 9.09 (s, 2H). LCMS m/z =502.2 [MH]⁺; RT [HPLC Method G1] = 9.739 min Enantiomer 2 155

HPLC Method B6; 7-{1-[1-(3,4-Difluoro 4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d] pyrimidin-4- amine (Example 228)¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.31 (m, 2H), 3.84 (s, 3H), 6.07(m, 1H), 6.61 (br s, 2H), 7.55 (s, 1H), 7.64 (m, 1H), 7.70 (m, 1H), 7.82(m, 1H), 8.08 (m, 2H), 8.23 (s, 1H), 8.96 (s, 1H). LCMS m/z = 481.2[MH]⁺; RT [HPLC Method B2] = 3.866 min Enantiomer 1 156

HPLC Method B6; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 228) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.31 (m, 2H), 3.84 (s, 3H), 6.06 (m, 1H), 6.25 (br s, 2H), 7.49 (s, 1H),7.62 (m, 1H), 7.72 (m, 1H), 7.82 (m, 1H), 8.10 (m, 2H), 8.16 (s, 1H),8.95 (s, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B2] = 5.840 minEnantiomer 2 157

HPLC Method B5; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 229) ¹HNMR (400 MHz, MeOD-d₄) 0.85 (t, 3H),2.31-2.39 (m, 2H), 3.94 (s, 3H), 5.99 (m, 1H), 7.34 (s, 1H), 7.40 (m,1H), 7.53 (d, 1H), 7.63 (m, 1H), 7.75 (m, 1H), 7.96 (s, 1H), 8.10 (s,1H), 8.50 (s, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B2] = 4.327min Enantiomer 1 158

HPLC Method B5; 7-{1-[1-(3,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 229) ¹HNMR (400 MHz, MeOD-d₄) 0.84 (t, 3H),2.33-2.38 (m, 2H), 3.93 (s, 3H), 5.99 (m, 1H), 7.33 (s, 1H), 7.39 (m,1H), 7.51 (d, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 7.96 (s, 1H), 8.10 (s,1H), 8.50 (s, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B2] = 5.926min Enantiomer 2 159

SFC Method A6; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- methoxypyrimidin-5-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 246) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H),2.32-2.40 (m, 2H), 3.97 (s, 3H), 6.08 (m, 1H), 6.32 (br s, 2H), 7.35 (m,1H), 7.54 (m, 1H), 7.62- 7.70 (m, 1H), 7.87 (m, 1H), 8.18 (s, 1H), 8.45(s, 1H), 8.68 (s, 1H), 8.76 (s, 1H). LCMS m/z = 464.2 [MH]⁺; [α]_(D)MeOH = +23.2°; RT [SFC Method A5] = 6.709 min Enantiomer 1 160

SFC Method A6; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- methoxypyrimidin-5-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 246) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H),2.32-2.40 (m, 2H), 3.97 (s, 3H), 6.08 (m, 1H), 6.32 (br s, 2H), 7.35 (m,1H), 7.54 (m, 1H), 7.62- 7.70 (m, 1H), 7.87 (m, 1H), 8.18 (s, 1H), 8.45(s, 1H), 8.68 (s, 1H), 8.76 (s, 1H). LCMS m/z = 464.2 [MH]⁺; [α]_(D)MeOH = −23.5°; RT [SFC Method A5] = 7.063 min Enantiomer 2 161

HPLC Method C21; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 235) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H),2.39 (m, 2H) 6.12 (m, 1H), 6.65 (br s, 2H), 7.34 (m, 1H) 7.68 (m, 1H),7.85-7.91 (m, 2H) 8.25 (s, 1H), 8.69 (d, 1H), 9.06 (s, 2H). LCMS m/z =502.0 [MH]⁺; RT [HPLC Method C9] = 4.472 min (+) optical rotationEnantiomer 1 162

HPLC Method C21; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 235) ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H),2.39 (m, 2H) 6.12 (m, 1H), 6.65 (br s, 2H), 7.34 (m, 1H) 7.68 (m, 1H),7.85-7.91 (m, 2H) 8.25 (s, 1H), 8.69 (d, 1H), 9.06 (s, 2H). LCMS m/z =502.0 [MH]⁺; RT [HPLC Method C9] = 4.841 min (−) optical rotationEnantiomer 2 163

HPLC Method B6; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyrimidin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 231) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.32-2.38 (m, 2H), 3.84 (s, 3H), 6.09 (t, 1H), 6.38 (br s, 2H), 7.35 (m,1H), 7.59-7.75 (m, 3H), 7.85 (m, 1H), 8.13 (s, 1H), 8.19 (s, 1H), 8.71(s, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B3] = 7.019 minEnantiomer 1 164

HPLC Method B6; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyrimidin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 231) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.32-2.36 (m, 2H), 3.84 (s, 3H), 6.09 (t, 1H), 6.40 (br s, 2H), 7.35 (m,1H), 7.59-7.75 (m, 3H), 7.85 (m, 1H), 8.13 (s, 1H), 8.19 (s, 1H), 8.71(s, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B3] = 9.528 minEnantiomer 2 165

HPLC Method B5, 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6- methoxypyrimidin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 232) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.37 (m, 2H), 3.98 (s, 3H), 6.09 (m, 1H), 6.51 (br s, 2H), 7.35 (m, 1H),7.61 (s, H), 7.73 (m, 2H), 7.96 (m, 1H), 8.03 (s, 1H), 8.22 (s, 1H),8.69 (d, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B2] = 4.230 minEnantiomer 1 166

HPLC Method B5; 7-{1-[1-(2,4-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6- methoxypyrimidin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 232) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.37 (m, 2H), 3.98 (s, 3H), 6.09 (m, 1H), 6.51 (br s, 2H), 7.35 (m, 1H),7.61 (s, H), 7.73 (m, 2H), 7.96 (m, 1H), 8.03 (s, 1H), 8.22 (s, 1H),8.69 (d, 1H). LCMS m/z = 481.2 [MH]⁺; RT [HPLC Method B2] = 10.052 minEnantiomer 2 167

HPLC Method F8; 5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{1[1-(2,4-difluorophenyl)-1H- 1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 230) ¹HNMR (400 MHz, DMSO-d₆) 0.87 (t, 3H),2.38-2.42 (m, 2H), 6.15 (t, 1H), 7.05 (dd, 1H), 7.35 (m, 1H), 7.65-7.71(m, 3H), 7.90 (m, 1H), 8.03 (s, 1H), 8.44 (s, 1H), 8.74 (s, 1H), 9.03(s, 2H). LCMS m/z = 484.2 [MH]⁺; RT [HPLC Method C5] = 3.056 minEnantiomer 1 168

HPLC Method F8; 5-[2-(Difluoromethyl) pyrimidin-5-yl]-7-{1-[1-(2,4-difluorophenyl)-1H- 1,2,3-triazol-4-yl]propyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 230) ¹HNMR (400 MHz, DMSO-d₆) 0.85 (t, 3H),2.37-2.42 (m, 2H), 6.12 (t, 1H), 6.79 (br s, 2H), 7.02 (dd, 1H), 7.34(m, 1H), 7.65 (m, 1H), 7.85 (m, 2H), 8.27 (s, 1H), 8.70 (s, 1H), 9.00(s, 2H). LCMS m/z = 484.1 [MH]⁺; RT [HPLC Method C5] = 4.166 minEnantiomer 2 169

HPLC Method C30; 7-{1-[1-(2,3-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 233) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.35 (m, 2H), 3.84 (s, 3H), 6.10 (m, 1H), 6.40 (br s, 2H), 7.44 (m, 1H),7.58-7.63 (m, 2H) 7.68 (m, 2H), 8.14 (s, 1H), 8.19 (s, 1H), 8.78 (s,1H). LCMS m/z = 481.1 [MH]⁺; RT [HPLC Method C10] = 2.190 min Enantiomer1 170

HPLC Method C30; 7-{1-[1-(2,3-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 233) ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.35 (m, 2H), 3.84 (s, 3H), 6.10 (m, 1H), 6.30 (br s, 2H), 7.44 (m, 1H),7.58-7.63 (m, 2H) 7.68 (m, 2H), 8.14 (s, 1H), 8.18 (s, 1H), 8.78 (s,1H). LCMS m/z = 481.1 [MH]⁺; RT [HPLC Method C10] = 2.511 min Enantiomer2 171

HPLC Method C30; 7-{1-[1-(2,5-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 234) ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.34 (m, 2H) 3.84 (s 3H), 6.09 (m, 1H), 6.30 (br s, 2H),7.50 (m, 1H), 7.57 (s, 1H) 7.60-7.65 (m, 2H), 7.84 (m, 1H), 8.14 (d,1H), 8.18 (s, 1H), 8.75 (d, 1H). LCMS m/z = 481.1 [MH]⁺; RT [HPLC MethodC10] = 2.214 min Enantiomer 1 172

HPLC Method C30; 7-{1-[1-(2,5-Difluoro phenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Example 234) ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.34 (m 2H) 3.84 (s 3H), 6.09 (m, 1H), 6.30 (br s, 2H),7.50 (m, 1H), 7.57 (s, 1H) 7.60-7.65 (m, 2H), 7.84 (m, 1H), 8.14 (d,1H), 8.18 (s, 1H), 8.75 (d, 1H). LCMS m/z = 481.1 [MH]⁺; RT [HPLC MethodC10] = 2.570 min Enantiomer 2 173

SFC Method C3; 5-cyclopropyl-7-{1-[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 236)¹HNMR (400 MHz, DMSO-d₆) 0.54 (m, 2H), 0.76-0.85 (m, 6H) 2.20- 2.33 (m,2H), 5.95 (m, 1H), 6.60 (br s, 2H), 7.02 (s, 1H), 7.42 (m, 1H),7.52-7.62 (m, 2H), 7.81 (m, 1H), 8.05 (s, 1H), 8.61 (s, 1H). LCMS m/z =378.4 [MH]⁺; [α]_(D) MeOH = −26.0°; RT [SFC Method C2] = 5.618 minEnantiomer 1 174

SFC Method D4; 7-{Cyclopropyl[1-(2- fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4- methoxypyrimidin-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 243) ¹HNMR (400 MHz, DMSO-d₆) 0.45 (m, 1H),0.58 (m, 2H), 0.71 (m, 1H), 1.96 (m, 1H), 3.94 (s, 3H), 5.46 (d, 1H),6.29 (s, 2H), 7.43 (m, 1H), 7.56-7.63 (m, 3H), 7.84 (m, 1H), 8.13 (s,1H), 8.43 (s, 1H), 8.76 (s, 2H). LCMS m/z = 458.1 [MH]⁺; [α]_(D) MeOH =+29.5°; RT [SFC Method D2] = 8.319 min Enantiomer 1 175

HPLC Method C33; 7-{1-[1-(2-Fluorophenyl)- 1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 271) ¹HNMR (400 MHz, DMSO-d₆) 0.83 (t, 3H), 2.31 (m, 2H),5.92 (t, 1H), 6.63 (br s, 2H), 7.31 (m, 1H), 7.43 (m, 2H), 7.74 (t, 1H),7.78 (s, 1H), 7.90 (s, 1H), 8.25 (s, 1H), 8.29 (s, 1H), 9.06 (s, 2H).LCMS m/z = 483.2 [MH]⁺; RT [HPLC Method C12] = 3.70 min Enantiomer 1 176

HPLC Method C33; 7-{1-[1-(2-Fluorophenyl)- 1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Example 271) ¹HNMR (400 MHz, DMSO-d₆) 0.83 (t, 3H), 2.31 (m, 2H),5.92 (t, 1H), 6.63 (br s, 2H), 7.31 (m, 1H), 7.43 (m, 2H), 7.74 (t, 1H),7.78 (s, 1H), 7.90 (s, 1H), 8.25 (s, 1H), 8.29 (s, 1H), 9.06 (s, 2H).LCMS m/z = 483.2 [MH]⁺; RT [HPLC Method C12] = 4.460 min Enantiomer 2177

HPLC Method C20B; 7-{1-[2-(2,4-Difluoro phenyl)-2H-imidazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 276) ¹HNMR (400 MHz, DMSO-d₆) 0.82 (t, 3H),2.26 (m, 1H), 2.34 (m, 1H), 5.88 (t, 1H), 6.59 (s, 2H), 7.13 (t, 1H),7.27 (s, 1H), 7.40 (t, 1H), 7.82 (s, 1H), 7.98 (t, 1H), 8.24 (s, 1H),9.05 (s, 2H), 12.22 (s, 1H). LCMS m/z = 501.2 [MH]⁺; RT [HPLC Method C2]= 2.994 min Enantiomer 1 178

HPLC Method C20B; 7-{1-[2-(2,4-Difluoro phenyl)-2H-imidazol-4-yl]propyl}-5-[2-(trifluoro methyl)pyrimidin-5-yl]-7H- pyrrolo[2,3-d]pyrimidin-4- amine (Example 276) ¹HNMR (400 MHz, DMSO-d₆) 0.82 (t, 3H),2.26 (m, 1H), 2.34 (m, 1H), 5.88 (t, 1H), 6.59 (s, 2H), 7.13 (t, 1H),7.27 (s, 1H), 7.40 (t, 1H), 7.82 (s, 1H), 7.98 (t, 1H), 8.24 (s, 1H),9.05 (s, 2H), 12.22 (s, 1H). LCMS m/z = 501.2 [MH]⁺; RT [HPLC Method C2]= 3.524 min Enantiomer 2 179

HPLC Method C34; 7-{1-[1-(2-Fluorophenyl)- 5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- (trifluoromethyl)pyrimidin- 5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 273) ¹HNMR (400 MHz, DMSO-d₆) 1.98 (d, 3H),2.17 (s, 3H), 6.31 (m, 1H), 6.65 (br s, 2H), 7.41 1H), 7.54-7.65 (m,3H), 7.93 (s, 1H), 8.26 (s, 1H), 9.07 (s, 2H). LCMS m/z = 484.2 [MH]⁺;RT [HPLC Method F5] = 3.796 min Enantiomer 1

Examples 183 and 184:7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

To a stirred solution of7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 59, 1 g, 2.226 mmol) in EtOH:H₂O (30 mL, 4:1) was added2-methoxypyrimidin-5-ylboronic acid (0.514 g, 3.34 mmol) and Na₂CO₃(0.944 g, 8.904 mmol). The reaction mixture was degassed with Ar for 15minutes and Pd(PPh₃)₄ (0.154 g, 0.134 mmol) added and the reactionheated at 90° C. for 6 hrs. The cooled mixture was concentrated todryness in vacuo, diluted with H₂O and extracted with EtOAc. Thecombined extracts were dried (Na₂SO₄), evaporated to dryness and theresidue purified by flash chromatography to afford the title compound(530 mg, 55%) as off white solid. This was combined with the product ofa parallel reaction (210 mg).

The product was purified by chiral SFC method A7, to afford Example 183,enantiomer 1, (−)7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(238.5 mg). ¹HNMR (400 MHz, DMSO-d₆): 1.95 (d, 3H), 3.96 (s, 3H), 6.32(q, 1H), 6.46 (br s, 2H), 6.92 (s, 1H), 7.35 (m, 1H), 7.41 (m, 1H), 7.57(m, 1H), 7.64 (s, 1H), 7.85 (m, 1H), 8.22 (s, 1H), 8.63 (s, 2H). LCMSm/z=432.3 [MH]⁺; RT [SFC method A8]=7.434 min; [α]_(D) MeOH=−11.7°.

Further elution provided Example 184, enantiomer 2, (+)7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(323.8 mg). ¹HNMR (400 MHz, DMSO-d₆): 1.95 (d, 3H), 3.96 (s, 3H), 6.32(q, 1H), 6.46 (brs, 2H), 6.92 (s, 1H), 7.35 (m, 1H), 7.41 (m, 1H), 7.57(m, 1H), 7.64 (s, 1H), 7.85 (m, 1H), 8.22 (s, 1H), 8.63 (s, 2H). LCMSm/z=432.3 [MH]⁺; RT [SFC method A8]=8.212 min; [α]_(D) MeOH=+12.6°.

Examples 185 and 186:7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

Step 1: To a solution of7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 49, 400 mg, 0.83 mmol) in dioxane (20 mL) and water (5 mL)under N₂, was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(250 mg, 0.91 mmol), Pd(dppf)Cl₂ (61 mg, 0.08 mmol), K₂CO₃ (344 mg, 2.49mmol) and the reaction heated at 85° C. for 6 hrs. The cooled mixturewas evaporated under reduced pressure and the residue purified by HPLCto afford7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(125 mg, 30%).

Step 2: The racemic product was further purified by chiral HPLC usingMethod C31 to afford7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1, Example 185, as a white solid (77 mg). ¹HNMR (400 MHz,DMSO-d₆): 0.86 (t, 3H), 2.39 (m, 2H), 6.13 (m, 1H), 6.78 (brs, 2H), 7.49(m, 1H), 7.65 (m, 1H), 7.79 (m, 1H), 7.92 (s, 1H), 8.27 (s, 1H), 8.68(s, 1H), 9.07 (s, 2H). LCMS m/z=502.1 [MH]⁺ RT [HPLC Method C10]=2.318min.

Further elution provided enantiomer 2, Example 186, as a white solid,(46 mg). ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.39 (m, 2H), 6.13 (m,1H), 6.84 (brs, 2H), 7.49 (m, 1H), 7.65 (m, 1H), 7.80 (m, 1H), 7.91 (s,1H), 8.26 (s, 1H), 8.75 (s, 1H), 9.07 (s, 2H). LCMS m/z=502.1 [MH]⁺ RT[HPLC Method C10]=2.871 min.

Examples 187 and 188:7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, Enantiomers 1 and 2

Step 1:7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared from7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 50) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine,following a similar procedure to that described in Step 1 of Example185/186.

Step 2: The compound from Step 1 was purified by chiral HPLC method F9,to afford7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1 ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.39 (m, 2H), 6.14(m, 1H), 6.72 (brs, 2H), 7.46 (m, 1H), 7.64 (m, 2H), 7.92 (s, 1H), 8.26(s, 1H), 8.77 (s, 1H), 9.07 (s, 2H).

LCMS m/z=502.1 [MH]⁺; RT [HPLC Method C10]=2.311 min.

and enantiomer 2; ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.39 (m, 2H),6.14 (m, 1H), 6.72 (br s, 2H), 7.46 (m, 1H), 7.64 (m, 2H), 7.92 (s, 1H),8.26 (s, 1H), 8.77 (s, 1H), 9.07 (s, 2H). LCMS m/z=502.1 [MH]⁺; RT [HPLCMethod C10]=2.843 min

Examples 189 and 190:7-{1-[1-(2,4-Difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 and 2

To a solution ofN′-(7-(1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 9, 2.8 g, 4.92 mmol) in dioxane was added NH₄OH (25 mL) andthe sealed tube was heated at 100° C. for 18 hrs. The solvent wasevaporated and the residue was diluted with EtOAc (150 mL) and water.The organic extract was washed with brine, dried (Na₂SO₄) and evaporatedto dryness in vacuo. The residue was purified by prep-HPLC to provide7-{1-[1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amineas a white solid (1.9 g, 75%). The solid was separated by HPLC using aCHIRALPAK IC column to afford enantiomer 1 (700 mg, 36%). ¹HNMR (400MHz, MeOD-d₄): 0.87 (t, 3H), 2.15 (s, 3H), 2.42 (m, 2H), 6.01 (t, 1H),7.11 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.72 (s, 1H), 8.17 (s, 1H),8.98 (s, 2H). LCMS m/z=516.2 [MH]⁺; RT [HPLC method C13]=2.297 min;

Further elution provided enantiomer 2 (725 mg, 38%). ¹HNMR (400 MHz,MeOD-d₄): 0.87 (t, 3H), 2.15 (s, 3H), 2.42 (m, 2H), 6.01 (t, 1H), 7.11(m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.72 (s, 1H), 8.17 (s, 1H), 8.98(s, 2H). LCMS m/z=516.2 [MH]⁺; RT [HPLC method C13]=3.405 min.

Example 191:7-{1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(5-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred solution of7-{1-[3-(2-Fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 59, 100 mg, 0.226 mmol),2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (105mg, 0.445 mmol) and K₃PO₄ (189 mg, 0.89 mmol) in dioxane:water (2.5 mL,4:1) was degassed with N₂ for 30 mins. To this was added Pd₂(dba)₃(20.38 mg, 0.022 mmol) followed by SPhos (18.25 mg, 0.045 mmol) and themixture degassed for another 5 min and heated to 110° C. for 16 hr. Thereaction mixture was partitioned between water and EtOAc, and the waterfurther extracted with EtOAc. The combined organics were washed withwater, brine, dried (Na₂SO₄) and evaporated to dryness in vacuo. Theresidue was purified by column chromatography on silica gel eluting withMeOH:DCM (0:100-1:10) followed by prep-TLC to afford the title compoundas an off-white solid (18.5 mg, 19.3%). ¹HNMR (400 MHz, DMSO-d₆): 1.98(d, 3H), 3.94 (s, 3H), 6.33 (q, 1H), 6.90 (m, 1H), 7.30-7.45 (m, 3H),7.56 (q, 1H), 7.86 (m, 1H), 8.13 (brs, 1H), 8.27 (s, 1H), 8.33 (m, 1H),8.89 (s, 1H). LCMS m/z=432.2 [MH]⁺

Example 192:4-(4-Amino-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile

A stirred solution of7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 58, 100 mg, 0.23 mmol), (4-cyano-3-fluorophenyl)boronicacid (76.76 mg, 0.46 mmol) and Na₂CO₃ (97.47 mg, 0.92 mmol) inEtOH:water (4:1, 5 mL) was degassed with N₂ for 30 mins. To this wasadded Pd(PPh₃)₄ (15.9 mg, 0.014 mmol) and the resulting brown suspensionwas heated to 110° C. for 6 hr. The reaction mixture was cooled to rt,diluted with water and extracted with EtOAc (2×). The combined extractswere washed with water, brine, dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with MeOH:DCM (0:100-1:10) to afford the titlecompound as an off white solid (24 mg, 24.4%). ¹HNMR (400 MHz, MeOH-d₄):5.58 (s, 2H), 7.32-7.44 (m, 3H), 7.56 (m, 1H), 7.60-7.67 (m, 3H), 7.93(t, 1H), 8.09 (m, 1H), 8.40 (s, 1H). LCMS m/z=428 [MH]⁺

Example 193:7-{[2-(2-Fluorophenyl)-1H-imidazol-5-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as a white solid (235 mg, 41%) in ananalogous manner to Example 192 using7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 68,500 mg, 1.15 mmol) and (2-methoxypyridin-3-yl)boronicacid (352 mg, 2.3 mmol). ¹HNMR (400 MHz, MeOD-d₄): 3.92 (s, 3H), 5.40(s, 2H), 7.03 (dd, 1H), 7.12-7.30 (m, 4H), 7.40 (q, 1H), 7.67 (dd, 1H),7.95 (t, 1H), 8.12-8.22 (m, 3H). LCMS m/z=416 [MH]⁺

Example 194:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred solution of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 150 mg, 0.345 mmol) in EtOH:water (4:1, 3 mL),(2-methoxy-6-methylpyridin-3-yl)boronic acid (86.32 mg, 0.517 mmol) andNa₂CO₃ (146.14 mg, 1.37 mmol) was degassed with Ar for 15 minutes andPd(PPh₃)₄ (39.8 mg, 0.034 mmol) added and reaction mixture heated at100° C. for 16 hours. The reaction was cooled to rt, diluted with waterand extracted with EtOAc. The combined organics were dried (Na₂SO₄) andevaporated to dryness in vacuo. The residue was purified flashchromatography and prep-TLC to afford the title compound as an off-whitesolid (26 mg, 15%). ¹HNMR (400 MHz, DMSO-d₆): 2.44 (s, 3H), 3.84 (s,3H), 5.55 (s, 2H), 6.00 (brs, 2H), 6.92 (d, 1H), 7.36 (s, 1H), 7.42 (t,1H), 7.51-7.61 (m, 3H), 7.82 (t, 1H), 8.16 (s, 1H), 8.61 (s, 1H). LCMSm/z=431 [MH]⁺

Example 195:5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared in an analogous manner to Example 194using7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95) and5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Preparation 140) and obtained as a white solid (25 mg, 20.8%). ¹HNMR(400 MHz, DMSO-d₆): 3.85 (s, 3H), 5.56 (s, 2H), 6.23 (br s, 2H), 7.42(t, 1H), 7.47-7.63 (m, 4H), 7.81 (t, 1H), 8.11 (d, 1H), 8.17 (s, 1H),8.62 (s, 1H). LCMS m/z=435 [MH]⁺

Example 196:5-[2-(Difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred solution of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 100 mg, 0.23 mmol),2-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(155 mg, 0.575 mmol) and CS₂CO₃ (299.7 mg, 0.92 mmol) in DMF:water (4:1,10 mL) was degassed with Ar for 15 mims. PdCl₂(dppf).DCM (37.5 mg, 0.046mmol) was added and reaction mixture was heated at 100° C. for 6 hrs.The reaction was cooled to rt, diluted with water and extracted withEtOAc. The combined organics were dried (Na₂SO₄) and evaporated todryness in vacuo. The residue was purified flash chromatography andprep-TLC to afford the title compound as an off-white solid (12.5 mg,12.02%). ¹HNMR (400 MHz, DMSO-d₆): 5.59 (s, 2H), 6.22 (br s, 2H),7.32-7.90 (m, 8H), 8.19 (s, 1H), 8.22 (m, 1H), 8.61 (m, 1H). LCMSm/z=453 [MH]⁺

Example 197:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1,3-oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as a white solid (15 mg, 11.6%) in ananalogous manner to Example 196 using7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 150 mg, 0.345 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (168.1 mg, 0.862mmol). ¹HNMR (400 MHz, DMSO-d₆): 5.62 (s, 2H), 7.32-7.43 (m, 3H), 7.54(m, 1H), 7.74 (s, 1H), 7.81 (t, 1H), 8.21 (s, 1H), 8.26 (s, 1H). 8.40(d, 1H). LCMS m/z=377.0 [MH]⁺

Example 198:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-(2,5-dihydrofuran-2-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Example 199, 40 mg, 0.106 mmol) in MeOH (2.0 mL) was added 50% moistPd/C (20.0 mg) and the reaction mixture was stirred at rt under H₂ for16 hr. The reaction mixture was filtered through Celite® and the solventwas evaporated to dryness in vacuo. The residue was purified by prep-TLCto afford the title compound as an off-white solid (10 mg, 32%). ¹HNMR(400 MHz, DMSO-d₆): 1.24 (s, 1H), 1.87-2.23 (m, 3H), 3.83 (m, 1H), 3.94(m, 1H), 4.96 (m, 1H), 5.47 (s, 2H), 6.79 (brs, 2H), 7.24 (s, 1H), 7.42(t, 1H), 7.53-7.62 (m, 2H), 7.81 (t, 1H), 8.11 (s, 1H), 8.55 (s, 1H).LCMS m/z=380 [MH]⁺

Example 199:5-(2,5-Dihydrofuran-2-yl)-7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a degassed solution of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 2.0 g, 4.59 mmol) was added Bu₄NCl (1.59 g, 5.74 mmol),NaOAc (1.31 g, 13.78 mmol), 2,3-dihydrofuran (3.47 mL, 45.95 mmol) andPd(OAc)₂ (1.03 g, 4.59 mmol). Degassing was discontinued for 15 min andthe resulting reaction mixture was heated to 50° C. for 2 hrs. Thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organics were washed with water, brine, dried (Na₂SO₄) andevaporated to dryness in vacuo. The residue was purified by columnchromatography on silica gel followed by prep-HPLC, to afford the titlecompound as an off white solid (80 mg, 4.6%). ¹HNMR (400 MHz, DMSO-d₆)4.67 (s, 2H), 5.47 (s, 2H), 6.02 (br s, 1H), 6.22 (m, 2H), 6.67 (br s,2H), 7.42 (t, 1H), 7.51-7.64 (m, 2H), 7.81 (t, 1H), 8.12 (s, 1H), 8.56(s, 1H). LCMS m/z=378 [MH]⁺

Example 200:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a degassed solution of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 2 g, 4.56 mmol) in MeCN:H₂O (80 mL, 4:1) was added(4-methoxypyrimidin-5-yl)boronic acid (1.19 g, 5.055 mmol) followed byCsF (3.49 g, 23.0 mmol). The resulting mixture was degassed with Ar for15 minutes and Pd(PPh₃)₄ (0.69 g, 0.597 mmol) was added and reactionmixture heated at 70° C. for 6 hours. The reaction mixture was dilutedwith water and extracted with DCM. The combined organics were dried(Na₂SO₄) and evaporated to dryness in vacuo. The residue was purified bycolumn chromatography on silica gel, followed by trituration withDCM-ether to afford the title compound as off white solid (1.5 g, 78%).¹HNMR (400 MHz, DMSO-d₆) 3.93 (s, 3H), 5.57 (s, 2H), 6.33 (s, 2H), 7.42(t, 1H), 7.48 (s, 1H), 7.52-7.62 (m, 2H), 7.81 (t, 1H), 8.17 (s, 1H),8.41 (s, 1H), 8.62 (d, 1H), 8.75 (s, 1H). LCMS m/z=418 [MH]⁺

Example 201: No Example 201 was Prepared Example 202:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxypyridin-3-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 54, 150.0 mg, 0.334 mmol) in EtOH-water (4:1) (8.0 mL) wasadded2-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(153.2 mg, 1.002 mmol) and Na₂CO₃ (106.16 mg, 1.002 mmol). The reactionmixture was degassed with Ar for 15 min and Pd(PPh₃)₄ (38.6 mg, 0.033mmol) added and degassed with Ar for 5 min and heated to 90° C. for 6 h.The reaction mixture was filtered through Celite® washing through with5% MeOH/DCM. The combined organics were evaporated to dryness underreduced pressure and the residue azeotroped with toluene. The solid wastriturated with Et₂O and purified by prep TLC (3% MeOH:DCM) to affordthe title compound as an off white solid (45.0 mg, 31.31%). ¹HNMR (400MHz, MeOD-d₄) 2.53 (s, 3H), 3.92 (s, 3H), 5.59 (s, 2H), 7.03 (dd, 1H),7.24 (s, 1H), 7.38 (m, 2H), 7.54 (m, 1H), 7.67 (dd, 1H), 7.81 (t, 1H),8.14 (dd, 1H), 8.37 (d, 1H). LCMS m/z=431 [MH]⁺

Example 203:7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off-white solid (32.19 mg, 16.8%)in an analogous manner to that described in Example 202 using7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 54, 200.0 mg, 0.445 mmol) and4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine(94 mg, 0.49 mmol). ¹HNMR (400 MHz, CDCl₃) 2.60 (s, 3H), 4.04 (s, 3H),4.91 (s, 2H), 5.60 (s, 2H), 7.25-7.32 (m, 3H), 7.44 (m, 1H), 7.92 (m,1H), 8.16 (d, 1H), 8.46 (s, 1H), 8.75 (s, 1H). LCMS m/z=432 [MH]⁺

Example 204:5-(2-(difluoromethyl)pyrimidin-5-yl)-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 55, 375 mg, 0.86 mmol) in DMF (20 mL) was added under N₂,2-(difluoromethyl)pyrimidin-5-ylboronic acid (0.3 g, 1.73 mmol), Na₂CO₃solution (5 mL) and Pd(dppf)Cl₂ (63 mg, 0.086 mmol). The reaction wasstirred at 100° C. for 6 hours then was water added to the cooledmixture. The reaction mixture was extracted with EtOAc (40 mL×2) and thecombined organics washed with brine, dried and evaporated to dryness invacuo. The residue was purified by column chromatography over silica gel(DCM:MeOH=9:1) to give the title compound (200 mg, 58%). ¹HNMR (400 MHz,DMSO-d₆) 5.38 (s, 2H), 6.59 (br s, 2H), 7.05 (t, 1H), 7.33-7.50 (m, 3H),7.74 (m, 2H), 7.77 (s, 1H), 8.30 (s, 2H), 8.98 (s, 2H). LCMS m/z=437.1[MH

Example 205:5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 56, 360 mg, 0.80 mmol) in DMF (30 mL) was added2-(difluoromethyl)pyrimidin-5-ylboronic acid (279 mg, 1.60 mmol), Na₂CO₃solution (8 mL). Pd(dppf)Cl₂ (59 mg, 0.08 mmol) was added under N₂. Thereaction was stirred at 100° C. overnight, cooled and water added. Themixture was extracted with EtOAc (50 mL×2) and the combined extractswashed with brine, dried and evaporated to dryness in vacuo. The residuewas purified by column chromatography over silica gel (DCM:MeOH=10:1) togive the title compound (300 mg, 70%). ¹HNMR (400 MHz, DMSO-d₆) 1.88 (d,3H), 6.17 (q, 1H), 6.53 (br s, 2H), 7.00 (t, 1H), 7.30-7.45 (m, 3H),7.74 (t, 1H), 7.80 (d, 2H), 8.26 (m, 2H), 8.99 (s, 2H). LCMS m/z=451.2[MH]⁺

Example 206:7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred, degassed solution of7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 100.0 mg, 0.229 mmol) in MeCN/water (8.0 mL) was added2-methoxy-6-trifluoromethylpyridine-3-boronic acid (65.6 mg, 0.298mmol), CsF (138.5 mg, 0.917 mmol) and the mixture degassed with N₂ for 5min. Pd(PPh₃)₄ (26.5 mg, 0.023 mmol) was added and the mixture degassedwith N₂ for an additional 5 min. The reaction was heated to 90° C. for16 hr, additional 2-methoxy-6-trifluoromethylpyridine-3-boronic acid(0.5 eq) was added and the reaction heated to 90° C. for a further 16hr. The reaction mixture was filtered through Celite® and evaporated todryness in vacuo. The residue was purified by repeated preparative TLC(70% EtOAc in hexane) to afford the title compound as a brown solid(13.0 mg, 11.7%). ¹HNMR (400 MHz, CDCl₃) 4.03 (s, 3H), 5.04 (s, 1H),5.63 (s, 2H), 7.26-7.50 (m, 6H), 7.72 (d, 1H), 7.90 (t, 1H), 8.17 (d,1H), 8.38 (s, 1H). LCMS m/z=485 [MH]⁺

Example 207:7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(3-methoxypyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 95, 200 mg, 0.46 mmol) and3-methoxy-2-(tributylstannyl)pyridine (845.8 mg, 2.298 mmol) in DMF (10mL) was added dry LiCl (58.4 mg, 1.379 mmol) and the resulting mixturedegassed with Ar for 15 minutes. Pd(PPh₃)₄ was added and reactionmixture was heated at 100° C. for 16 hours. The reaction was quenchedwith water, extracted with EtOAc, dried (Na₂SO₄) and concentrated invacuo and the residue purified by flash chromatography followed by prepHPLC to afford the title compound as an off-white solid (11.5 mg, 6%).¹HNMR (400 MHz, DMSO-d₆) 3.98 (s, 3H), 5.60 (s, 2H), 7.18 (brs, 1H),7.27 (dd, 1H), 7.41 (t, 1H), 7.51-7.63 (m, 3H), 7.80 (t, 1H), 8.11 (s,1H), 8.18 (d, 1H), 8.32 (s, 1H), 8.58 (s, 1H), 9.95 (br s, 1H). LCMSm/z=417 [MH]⁺

Example 208:5-(4-Chlorophenyl)-7-{1-[1-(3-methylphenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a degassed solution of7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine(Preparation 77, 50 mg, 0.30 mmol), was added 0.5(M) soln. of3-methylphenylazide (0.58 mL, 0.286 mmol) in t-butyl ether, DIPEA (0.27mL, 2.9 mmol) in t-BuOH:toluene (4:1, 5 mL) and CuI (16 mg, 0.145 mmol)and the reaction heated at 100° C. for 16 hr in a sealed tube. Thecooled mixture was filtered through a pad of Celite®, the filtratediluted with EtOAc (70 mL), washed with water (25 mL) and brine (25 mL).The organic solution was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by prep TLC to afford the title compoundas an off white solid (12.4 mg, 17%). ¹HNMR (400 MHz, MeOD-d₄) 2.00 (d,3H), 2.42 (s, 3H), 6.29-6.35 (m, 1H), 7.30 (m, 1H), 7.34 (s, 1H),7.39-7.48 (m, 5H), 7.60 (m, 1H), 7.65 (m, 1H), 8.20 (d, 1H), 8.51 (s,1H). LCMS m/z=430.0 [MH]⁺

Example 209:5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

N′-[7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidoformamide(Preparation 13, 175 mg, 0.48 mmol), 2-fluorophenyl azide (104 mg, 0.72mmol), CuI (50.6 mg, 0.263 mmol) and DIPEA (0.84 mL, 4.8 mmol) weresuspended in t-BuOH (1 mL) and toluene (4 mL) and the reaction stirredat rt for 18 hrs. The mixture was partitioned between EtOAc and water,the organic layer washed with brine and dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with EtOAc:Heptane (70:100 to100:0). The product was treated with TFA followed by ammonia hydroxide,then the mixture diluted with water and extracted with EtOAc. Thecombined organic extracts were washed with brine, dried (MgSO₄) andconcentrated under reduced pressure to afford the title compound, as asolid (130 mg, 60%). ¹HNMR (400 MHz, DMSO-d₆) 1.85 (d, 3H), 3.35 (s,3H), 6.09 (brs, 2H), 6.33 (m, 1H), 7.38-7.48 (m, 6H), 7.54-7.62 (m, 2H),7.80 (m, 1H), 8.64 (m, 1H). LCMS m/z=448.1 [MH]⁺

Example 210:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred suspension of7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 41, 60 g, 0.137 mol), (2-methoxy-pyridin-3-yl) boronic acid(31.6 g, 0.206 mol) and Na₂CO₃ (58.4 g, 0.551 mol) in EtOH: Water (750mL, 4:1) was degassed under N₂ for 30 minutes. Pd(PPh₃)₄ (15.97 g,0.0137 mol) was added and the reaction heated at 90° C. for 16 hr underN₂. The cooled reaction was diluted with water (1 L) and EtOAc (500 mL),the layers separated and the aqueous extracted with EtOAc (2×1 L). Thecombined organic layers were washed with water (2×250 mL) followed bybrine, dried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel eluting withsaturated ammonical MeOH: DCM, 0:100-10:100, to afford compound thetitle compound as a white solid (35 g, 61.4%). ¹HNMR (400 MHz, DMSO-d₆)3.86 (s, 3H), 5.56 (s, 2H), 6.05 (brs, 2H), 7.08 (m, 1H), 7.42 (m, 2H),7.53-7.65 (m, 3H), 7.81 (m, 1H), 8.17 (s, 2H), 8.63 (s, 1H). LCMSm/z=417.1 [MH]⁺

Example 211:5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A suspension of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 45, 3.0 g, 6.47 mmol), 4-chlorophenylboronic acid (2.02 g,12.9 mmol), and Na₂CO₃ (2.7 g, 25.9 mmol) in EtOH (13.5 mL) and H₂O (3.5mL) was degassed with N₂. Pd(PPh₃)₄ (449 mg, 0.39 mmol) was added andthe reaction stirred at 80° C. for 2 hrs. The cooled mixture wasfiltered through Celite®, washing through with 10% MeOH:DCM and thefiltrate evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel eluting with MeOH:DCM(1:99) to afford the title compound as a yellow sold (1.9 g, 65.5%).¹HNMR (400 MHz, DMSO-d₆) 0.83 (t, 3H), 2.36 (m, 2H), 6.10 (m, 1H),6.22-6.35 (brs, 2H), 7.41 (m, 1H), 7.42-7.61 (m, 7H), 7.81 (m, 1H), 8.22(s, 1H), 8.72 (s, 1H). LCMS m/z=447.9 [MH]⁺

Example 212:5-[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as an off white solid (550 mg, 34%),from7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42) and 4-cyclopropyloxyphenyl boronic acid, following theprocedure described in Example 211. ¹HNMR (400 MHz, DMSO-d₆) 0.68 (m,2H), 0.78 (m, 2H), 1.90 (d, 3H), 3.87 (m, 1H), 6.10 (brs, 2H), 6.32 (q,1H), 7.14 (m, 2H), 7.37-7.44 (m, 4H), 7.55-7.61 (m, 2H), 7.81 (m, 1H),8.18 (s, 1H), 8.65 (s, 1H). LCMS m/z=456.0 [MH]⁺

Example 213:5-[6-(Cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as an off white solid (590 mg, 25%) from7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42) and 6-cyclopropyloxy-3-pyridinyl boronic acid followinga similar method to that described in Example 211, except 3 eq ofboronic acid were used. ¹HNMR (400 MHz, DMSO-d₆) 0.69 (m, 2H), 0.78 (m,2H), 1.91 (d, 3H), 4.22 (m, 1H), 6.18 (brs, 2H), 6.32 (q, 1H), 6.93 (d,1H), 7.43 (m, 1H), 7.47 (s, 1H), 7.53-7.61 (m, 2H), 7.77-7.84 (m, 2H),8.18 (s, 1H), 8.26 (m, 1H), 8.65 (s, 1H). LCMS m/z=457.1 [MH]⁺

Example 214:5-[4-(Cyclopropoxy)phenyl]-7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as a white solid (26 mg, 37%) from7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42) and 4-cyclopropoxyphenyl boronic acid, following ananalogous method to that described in Example 211. ¹HNMR (400 MHz,DMSO-d₆) 0.67 (m, 2H), 0.79 (m, 2H), 1.95 (d, 3H), 3.87 (m, 1H), 6.35(m, 1H), 7.13 (d, 2H), 7.37-7.42 (m, 3H), 7.69-7.73 (m, 1H), 8.12-8.19(m, 2H), 8.48 (m, 1H), 8.74 (s, 1H). LCMS m/z=457.0 [MH]⁺

Examples 215 to 234

A mixture of the appropriate iodo starting material (1 eq), boronic acidor ester (1.5-2.0 eq), Pd(dppf)Cl₂ (0.1 eq) and K₂CO₃ (1-3 eq) indioxane:H₂O (4:1 v/v) was degassed with N₂. The reaction mixture wasstirred at 90° C. under N₂ for 2-4 hr. The cooled mixture was pouredinto water and extracted with DCM. The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel eluting withDCM:MeOH to afford the title compound.

Ex. No. Structure Starting Materials Analytical Data 215^(b,c)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl] ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 42) and 2-methoxypyridine- 3-boronic acid ¹HNMR (400 MHz, DMSO-d₆) 1.90 (d, 3H), 3.86 (s,3H), 6.04 (br s, 2H), 6.31 (m, 1H), 7.06 (m, 1H), 7.42 (m, 2H),7.53-7.65 (m, 3H), 7.82 (m, 1H), 8.17 (s, 2H), 8.65 (s, 1H). LCMS m/z =431.2 [MH]⁺ 216^(d)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4- yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 42) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2- (trifluoromethyl) pyrimidine¹HNMR (400 MHz, DMSO-d₆) 1.95 (d, 3H), 6.35 (m, 1H), 6.66 (br s, 2H),7.43 (m, 1H), 7.55- 7.61 (m, 2H), 7.80 (m, 1H), 7.86 (s, 1H), 8.25 (d,1H), 8.67 (s, 1H), 9.05 (s, 2H). LCMS m/z = 470.1 [MH]⁺ 217

7-{1-[1-(2,4-difluoro phenyl)-1H-1,2,3-triazol- 4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 44) and 2-(trifluoromethyl)pyrimidin- 5-ylboronic acid ¹HNMR (400 MHz, DMSO-d₆)1.97 (d, 3H), 6.40 (m, 1H), 7.35 (m, 1H), 7.67 (m, 1H), 7.85- 8.08 (m,4H), 8.51 (m, 1H), 8.51 (s, 1H), 9.10 (s, 2H). LCMS m/z = 488.2 [MH]⁺218^(d,e)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl] ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 42) and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole LCMS m/z = 390.1[MH]⁺ 219

5-iodo-7-[1-(1-phenyl- 1H-1,2,3-triazol-4- yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 51) and 2- (trifluoromethyl)pyrimidin-5-ylboronic acid ¹HNMR (400 MHz, DMSO-d₆) 0.88 (t, 3H),2.35-2.44 (m, 2H), 6.13 (t, 1H), 7.50 (m, 1H), 7.60 (m, 2H), 7.88 (d,2H), 8.02 (m, 1H), 8.45 (m, 1H), 8.97 (s, 1H), 9.10 (s, 2H). 220

5-iodo-7-[1-(1-phenyl- 1H-1,2,3-triazol-4- yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 51) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)- 2-(trifluoro methyl)pyrimidine ¹HNMR (400MHz, DMSO-d₆) 0.87 (t, 3H), 2.36-2.44 (m, 2H), 3.90 (s, 3H), 6.12 (t,1H), 6.92 (d, 1H), 7.48 (m, 1H), 7.60 (m, 2H), 7.80 (m, 2H), 7.90 (m,2H), 8.26 (s, 1H), 8.49 (s, 1H), 8.98 (s, 1H). 221^(a)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl] propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 45) and2-(difluoromethyl)-5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrimidine ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H), 2.36 (m, 2H), 6.12(m, 1H), 6.28 (m, 1H), 7.18 (d, 1H), 7.45 (m, 1H), 7.52-7.63 (m, 3H),7.75 (d, 1H), 7.84 (m, 1H), 7.98 (m, 1H), 8.22 (s, 1H), 8.36 (s, 1H),8.72 (s, 1H). LCMS m/z = 466.2 [MH]⁺ 222

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4- yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-amine (Preparation 45) and 2-(dimethylamino)pyrimidin-5- ylboronic acid ¹HNMR (400 MHz, DMSO-d₆) 0.83 (t, 3H),2.32 (m, 2H), 3.84 (s, 3H), 6.09 (t, 1H), 6.22 (br s, 2H), 7.42 (m, 1H),7.54-7.62 (m, 4H), 7.82 (m, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.70 (s,1H). LCMS m/z = 463.2 [MH]⁺ 223

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4- yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 45) and5-fluoro-2-methoxy- 3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine ¹HNMR (400 MHz, DMSO-d₆) 0.83 (t, 3H), 2.32 (m, 2H), 3.84 (s,3H), 6.09 (t, 1H), 6.22 (br s, 2H), 7.42 (m, 1H), 7.54-7.62 (m, 4H),7.82 (m, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.70 (s, 1H). LCMS m/z = 463.2[MH]⁺ 224^(d)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl] propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 45) and2-(trifluoromethyl) pyrimidin-5-ylboronic acid ¹HNMR (400 MHz, CDCl₃)0.98 (t, 3H), 2.44-2.59 (m, 2H), 6.09 (t, 1H), 7.30 (m, 2H), 7.43 (m,1H), 7.61 (s, 1H), 7.93 (m, 1H), 8.14 (s, 1H), 8.43 (s, 1H), 9.05 (s,2H). LCMS m/z = 484.2 [MH]⁺ 225^(a,c)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl] propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 45) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)oxazole ¹HNMR (400 MHz, CDCl₃)0.94 (t, 3H), 2.40-2.57 (m, 2H), 5.75 (s, 2H), 6.12 (t, 1H), 7.22-7.32(m, 3H), 7.41 (m, 1H), 7.66 (s, 1H), 7.93 (m, 2H), 8.07 (s, 1H), 8.34(s, 1H). LCMS m/z = 405.2 [MH]⁺ 226^(d,e)

7-{1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4- yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 45) and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole ¹HNMR (400 MHz,CDCl₃) 0.96 (t, 3H), 2.46-2.62 (m, 2H), 4.12 (m, 1H), 5.30 (s, 2H), 6.11(m, 1H), 6.56 (d, 1H), 7.23-7.31 (m, 2H), 7.45 (m, 1H), 7.63 (m, 2H),7.89 (m, 1H), 8.06 (s, 1H), 8.28 (s, 1H). LCMS m/z = 404.1 [MH]⁺ 227^(c)

7-{1-[1-(3,4- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 48) and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 2-(trifluoro-methyl)pyrimidine ¹HNMR (400 MHz, CDCl₃) 0.99 (t, 3H), 2.45-2.48 (m,2H), 6.14 (t, 1H), 7.35 (m, 1H), 7.47 (m, 1H), 7.62 (m, 1H), 7.77 (s,1H), 8.08 (s, 1H), 8.22 (s, 1H), 9.02 (s, 2H). LCMS m/z = 502.1 [MH]⁺228

7-{1-[1-(3,4- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 48) and 5-fluoro-2-methoxy-3- pyridinylboronic acid ¹HNMR (400 MHz, MeOD-d₄) 0.99(t, 3H), 2.45-2.56 (m, 2H), 3.94 (s, 3H), 6.24 (t, 1H), 7.48-7.56 (m,1H), 7.64 (m, 1H), 7.72 (m, 2H), 7.90 (m, 1H), 8.12 (d, 1H), 8.37 (s,1H), 8.73 (s, 1H). LCMS m/z = 481.1 [MH]⁺ 229

7-{1-[1-(3,4- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 48) and 3-fluoro-2-methoxy-5-(4,4, 5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine ¹HNMR (400 MHz, DMSO-d₆) 0.80 (t, 3H), 2.45 (m, 2H), 6.15 (m,1H), 7.65-7.80 (m, 6H), 8.15 (m, 2H), 8.45 (m, 1H), 9.00 (s, 1H). LCMSm/z = 481.2 [MH]⁺ 230

7-{1-[1-(2,4- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 46) and 2-(difluoromethyl)-5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrimidine (Preparation 139) ¹HNMR (400 MHz, DMSO-d₆) 0.87 (t, 3H),2.38-2.45 (m, 2H), 6.15 (m, 1H), 6.91-7.18 (dd, 1H), 7.35 (m, 1H), 7.67-7.88 (m, 4H), 8.03 (s, 1H), 8.45 (s, 1H), 8.74 (s, 1H), 9.03 (s, 2H).LCMS m/z = 484.2 [MH]⁺ 231

7-{1-[1-(2,4- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 46) and 5-fluoro-2-methoxy-3- pyridinyl boronic acid ¹HNMR (400 MHz, MeOD-d₄) 0.99(t, 3H), 2.48-2.56 (m, 2H), 3.94 (s, 3H), 6.26 (t, 1H), 7.24 (m, 1H),7.36 (m, 1H), 7.64 (d, 1H), 7.75 (s, 1H), 7.85 (m, 1H), 8.13 (s, 1H),8.37 (s, 1H), 8.55 (s, 1H). LCMS m/z = 481.1 [MH]⁺ 232

7-{1-[1-(2,4-difluoro phenyl)-1H-1,2,3-triazol- 4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 46) and3-fluoro-2-methoxy- 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine 233

7-{1-[1-(2,3- difluorophenyl)-1H-1,2,3- triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-amine (Preparation 50) and 5-fluoro-2-methoxy-3-(4,4, 5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine LCMS m/z = 481.2 [MH]⁺ 234

7-{1-[1-(2,5-difluoro phenyl)-1H-1,2,3-triazol- 4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Preparation 49) and5-fluoro-2-methoxy- 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine LCMS m/z = 481.1 [MH]⁺ ^(a)DMF was used as the reactionsolvent, ^(b)Cs₂CO₃ was used instead of K₂CO₃, ^(c)PdCl₂(dppf). DCM wasused instead of Pd(dppf)Cl₂, ^(d)Na₂CO₃ was used as the base,^(e)DMF/Water (5:1 v/v) was used as the reaction solvent

Example 235:7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of7-(1-(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 46, 55 g, 114.33 mmol) in dioxane (1100 ml) and H₂O (275ml) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(37.6 g, 137.2 mmol), Na₂CO₃ (36.3 g, 343 mmol) and Pd(PPh₃)₄ (13.2 g,11.43 mmol) and the reaction stirred at 90° C. for 10 hrs under N₂. Thecooled mixture was concentrated in vacuo and the residue diluted withEtOAc. The residue was purified by silica gel column (using pet.ether:EtOAc=1:10) to give the title compound as a white solid (32.8 g,57%). ¹HNMR (400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.35-2.43 (m, 2H), 6.13(t, 1H), 6.67 (brs, 2H), 7.34 (m, 1H), 7.68 (m, 1H), 7.90 (m, 2H), 8.25(s, 1H), 8.70 (d, 1H), 9.07 (s, 2H). LCMS m/z=502.1 [MH]⁺

Example 236:5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 45, 2.0 g, 4.32 mmol) and K₃PO₄ (4.58 g, 21.59 mmol) indioxane:H₂O (2:1, 60 mL) was added cyclopropyl boronic acid (927 mg,1.79 mmol) and the mixture degassed under Ar. PdCl₂(dppf)₂.DCM (705 mg,0.86 mmol) was added and the reaction stirred at 80° C. for 16 hr N₂.The cooled mixture was concentrated under reduced pressure, the residuedissolved in EtOAc, washed with water followed by brine, dried (Na₂SO₄)and concentrated. The crude product was purified twice by prep-TLCeluting with MeOH:DCM to afford the title compound as a brown solid (250mg, 15.34%). ¹HNMR (400 MHz, MeOD-d₄) 0.64 (m, 2H), 0.84-0.92 (m, 5H),1.98 (m, 1H), 2.30-2.43 (m, 2H), 5.95 (m, 1H), 7.02 (s, 1H), 7.36-7.43(m, 2H), 7.55 (m, 1H), 7.81 (m, 1H), 8.07 (s, 1H), 8.33 (s, 1H). LCMSm/z=378.4 [MH]⁺

Example 237:5-(6-Cyclopropoxypyridin-3-yl)-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 44, 1 g, 2.14 mmol) in dioxane (20 mL) and H₂O (5 mL) wasadded 6-cyclopropoxypyridin-3-ylboronic acid (462 mg, 2.57 mmol),Pd(PPh₃)₄ (247 mg, 0.214 mmol) and Na₂CO₃ (680 mg, 6.42 mmol) under N₂and the reaction heated to 90° C. for 5 hrs. The cooled mixture wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography eluting with DCM:MeOH (15:1) to afford thetitle compound as a white solid (500 mg 49%). LCMS m/z=475.1 [MH]⁺

Example 238:5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A suspension of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42, 36.1 g, 80.4 mmol), cyclopropyl boronic acid (14.2 g,161 mmol), S-Phos (13.5 g, 32.2 mmol), and K₃PO₄ (68.2 g, 321 mmol) indioxane (220 mL) and H₂O (110 mL) was degassed with N₂ for 30 min.Pd₂(dba)₃ (14.7 mmol, 16.1 mmol) was added and the reaction heated at100° C. for 18 hrs. The cooled mixture was partitioned between EtOAc(800 mL) and water (600 mL) the mixture filtered through Celite® and thelayers separated. The aqueous phase was extracted with EtOAc, thecombined organic extracts dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with acetone:DCM (30:70 to 0:100) to afford the title compoundas a light orange solid (6.74 g, 23%). ¹HNMR (400 MHz, DMSO-d₆)0.51-0.57 (m, 2H), 0.83 (m, 2H), 1.81 (d, 3H), 2.04 (m, 1H), 6.15 (q,1H), 6.56 (s, 2H), 6.97 (s, 1H), 7.42 (m, 1H), 7.53-7.61 (m, 2H), 7.81(m, 1H), 8.06 (s, 1H), 8.54 (s, 1H). LCMS m/z=364.24 [MH]⁺

Example 239:4-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorobenzonitrile

To stirred solution of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42, 1.5 g, 3.34 mmol) in dioxane-water (15:7.5 mL) wasadded 4-cyano-3-fluorophenylboronic acid (1.1 g, 6.67 mmol), potassiumphosphate (2.83 g, 13.35 mmol) and S-Phos (0.274 mg, 0.668 mmol). Themixture was degassed with N₂ for 15 min, Pd₂(dba)₃ (0.306 mg, 0.334mmol) added, the reaction degassed with N₂ for 10 min then stirred at100° C. for 1 hr. The cooled mixture was filtered through Celite® andthe filtrate concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel eluting with EtOAc:Hex (60:40) toafford the title compound as a brown solid (550 mg, 37.16%). ¹HNMR (400MHz, MeOD-d₄) 2.02 (d, 3H), 6.36 (m, 1H), 7.36-7.43 (m, 2H), 7.48 (m,2H), 7.52-7.58 (m, 2H), 7.76-7.82 (m, 2H), 8.25 (s, 1H), 8.42 (s, 1H).LCMS m/z=443.0 [MH]⁺

Example 240:5-[6-(Difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 45, 470 mg, 1.0 mmol), (2-difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)pyridine (385 mg,1.4 mmol), and CsF (623 mg, 4.1 mmol) in MeCN (8 mL) and H₂O (2 mL) wasdegassed under N₂. Pd(PPh₃)₄ (234 mg, 0.20 mmol) was added and thereaction stirred at 75° C. for 18 hrs. The cooled reaction was pouredinto water and extracted with EtOAc (2×). The combined organic extractswere dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel eluting withMeOH:DCM (0:100 to 10:90). The product was re-purified by columnchromatography on silica gel eluting with EtOAc:heptane (50:50 to 100:0)to afford the title compound as a yellow foam (211 mg, 43.8%). ¹HNMR(400 MHz, DMSO-d₆): 0.86 (t, 3H), 2.39 (m, 2H), 6.10 (m, 1H), 7.17 (d,1H), 7.43 (m, 1H), 7.52-7.62 (m, 2H), 7.74 (s, 1H), 7.82 (m, 1H), 7.89(s, 1H), 7.95 (d, 1H), 8.25 (s, 1H), 8.33 (s, 1H), 8.72 (s, 1H). LCMSm/z=481.3 [MH]⁺

Example 241:7-{1-[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as an orange foam in (240.5 mg, 54%)from7-{1-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 47, and4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine,following an analogous method to that described in Example 240. ¹HNMR(400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H), 3.92 (s, 3H), 6.08 (m,1H), 6.32 (brs, 2H), 7.42-7.50 (m, 3H), 7.95 (m, 2H), 8.18 (s, 1H), 8.41(s, 1H), 8.69 (s, 1H), 8.92 (s, 1H). LCMS m/z=446.2 [MH]⁺

Example 242:5-(4-Methoxypyrimidin-5-yl)-7-(1-{1-[4-(trifluoromethyl)pyridin-2-yl]-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as an off-white solid in (18 mg, 11%)from5-iodo-7-(1-{1-[4-(trifluoromethyl)pyridin-2-yl]-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 52), and4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine,following an analogous method to that described in Example 240. ¹HNMR(400 MHz, DMSO-d₆) 0.85 (t, 3H), 2.39 (m, 2H), 3.92 (s, 3H), 6.11 (q,1H), 6.32 (brs, 2H), 7.61 (s, 1H), 8.06 (m, 1H), 8.16 (s, 1H), 8.41 (m,3H), 8.74 (s, 1H), 8.97 (s, 1H). LCMS m/z=496.8 [MH]⁺

Example 243:7-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained as a light brown solid (900 mg, 44%)from7-{cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 53) and4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine,following the procedure described in Example 240. ¹HNMR (400 MHz,DMSO-d₆) 0.45 (m, 1H), 0.58 (m, 2H), 0.71 (m, 1H), 1.96 (m, 1H), 3.94(s, 3H), 5.46 (d, 1H), 6.29 (s, 2H), 7.43 (m, 1H), 7.56-7.63 (m, 3H),7.84 (m, 1H), 8.13 (s, 1H), 8.43 (s, 1H), 8.76 (s, 2H). LCMS m/z=458.0[MH]⁺

Example 244:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred suspension of7-{1-[1-(2-fluorophenyl)-1H-[1,2,3]triazol-4-yl]-propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 45, 100 g, 216.0 mmol) in MeCN:water (4 L, 4:1) was added4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine(71.36 g, 302.37 mmol) and the resulting reaction degassed with Ar for15 mins. Pd(PPh₃)₄ (24.95 g, 21.6 mmol), followed by CsF (131.23 g,863.9 mmol) were added and the reaction stirred at 70° C. for 1.5 hrs.The mixture was diluted with EtOAc, washed with water then brine and theorganic phase dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel eluting withMeOH:EtOAc (3:97) to afford a yellow solid. This was treated with hot(60° C.) EtOAc and charcoal, the mixture filtered through Celite® andthe filtrate evaporated under reduced pressure. The resulting solid wassuspended in MeCN, stirred for an hour, filtered, washed with MTBE anddried to afford the title compound as an off-white solid (39 g, 45%).¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H), 4.01 (s, 3H), 6.08(m, 1H), 6.32 (br s, 2H), 7.42 (m, 1H), 7.54-7.63 (m, 2H), 7.82 (m, 1H),8.16 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H), 8.75 (s, 1H). LCMS m/z=445.8[MH]⁺

Example 245:7-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A suspension of7-{1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 48, 400 mg, 0.86 mmol),4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine(275 mg, 1.16 mmol) and CsF (510 mg, 3.32 mmol) in MeCN (13 mL) and H₂O(4 mL) was degassed under N₂. Pd(PPh₃)₄ (100 mg, 0.09 mmol) was addedand the reaction heated at 70° C. for 2 hrs. The cooled reaction waspoured into water with a little brine and extracted twice with EtOAc.The combined organic layers were dried (MgSO₄) filtered and evaporatedunder reduced pressure. The resulting oil was purified by columnchromatography on silica gel eluting with MeOH:EtOAc (0:100 to 10:90) toafford the title compound as an orange foam (235 mg, 58.7%). ¹HNMR (400MHz, DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H), 3.94 (s, 3H), 6.08 (m, 1H),6.32 (brs, 2H), 7.47 (s, 1H), 7.72 (m, 1H), 7.82 (m, 1H), 8.10 (m, 1H),8.16 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H), 8.95 (s, 1H). LCMS m/z=465.3[MH]⁺

Example 246:7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained in 60% yield (241.4 mg), from7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 46) and4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine,following the procedure described in Example 245. ¹HNMR (400 MHz,DMSO-d₆) 0.84 (t, 3H), 2.33 (m, 2H), 3.94 (s, 3H), 6.09 (m, 1H), 6.32(br s, 2H), 7.36 (m, 1H), 7.54 (s, 1H), 7.68 (m, 1H), 7.90 (m, 1H), 8.16(s, 1H), 8.46 (s, 1H), 8.71 (s, 1H), 8.75 (s, 1H). LCMS m/z=464.2 [MH]⁺

Example 247:5-Cyclobutyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred solution of7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 42, 3 g, 6.68 mmol) in THF (150 mL) was degassed with Arfor 30 min. Pd(OAc)₂ (300 mg, 1.34 mmol), s-Phos (1.1 g, 2.67 mmol)followed by cyclobutyl zinc bromide (67 mL, 33.39 mmol, 0.5M in THF) wasadded and the reaction stirred at rt for 6 hr under N₂. The mixture wasdiluted with EtOAc, washed with water followed by brine, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified twice bycolumn chromatography on silica gel eluting with MeOH:DCM (2.5:97.5) toafford the title compound as an off white solid (800 mg, 31.75%). ¹HNMR(400 MHz, DMSO-d₆) 1.91-1.95 (m, 1H), 2.00-2.20 (m, 8H), 2.33-2.42 (m,2H), 5.07 (s, 2H), 6.31 (m, 1H), 7.23-7.31 (m, 2H), 7.41 (m, 1H), 7.92(m, 2H), 8.26 (s, 1H). LCMS m/z=378.2 [MH]⁺

Example 248:5-(4-Methoxypyrimidin-5-yl)-7-{1-[1-phenyl-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Aq. NH₄OH (66 mL) was added to a stirred solution ofN′-{5-(4-methoxypyrimidin-5-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-N,N-dimethylformimidamide(Preparation 6, 1 g, 2.072 mmol) in MeOH (33 mL) and the reactionstirred at 80° C. for 12 hr in a sealed tube. The cooled reactionmixture was diluted with DCM and washed with water followed by brine.The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with MeOH:DCM (3:97) to afford the title compound as anoff-white solid (530 mg, 59.55%). ¹HNMR (400 MHz, DMSO-d₆) 0.84 (t, 3H),2.32 (m, 2H), 3.91 (s, 3H), 6.06 (m, 1H), 6.36 (brs, 2H), 7.48 (m, 3H),7.59 (m, 2H), 7.88 (d, 1H), 8.17 (s, 1H), 8.43 (s, 1H), 8.75 (s, 1H),8.93 (s, 1H). LCMS m/z=427.6 [MH]⁺

Example 249:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

37% aqueous NH₄OH (0.4 mL) was added to a solution of4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine(Preparation 36, 38 mg, 0.07 mmol) in dioxane (0.2 mL) and the reactionheated at 130° C. for 45 min under microwave irradiation. The reactionwas poured into 10 mL of water and extracted with EtOAc. The combinedorganics were dried (MgSO₄), filtered, and concentrated in vacuo toprovide 37 mg of crude product. The crude material was purified by prepHPLC column to afford the title compound (1.4 mg, 4%). LCMS m/z=500.0[MH]⁺

Example 250:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

37% aq. NH₄OH (0.6 mL) was added to a solution of4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 35, 77 mg, 0.19 mmol) in dioxane (0.3 mL) and the reactionheated to 130° C. under microwave irradiation for 30 min. Additional 37%aq. NH₄OH (0.1 mL) was added and the reaction heated to 130° C. undermicrowave irradiation for a further 30 min. Water was added, the mixtureextracted with DCM and the combined organic extracts dried (MgSO₄),filtered, and concentrated in vacuo. The resulting light orange oil waspurified by column chromatography on silica gel eluting with MeOH:DCM(5:95 to 10:90) to afford the title compound (32.4 mg, 44.8%). ¹HNMR(400 MHz, DMSO-d₆) 1.88 (d, 3H), 4.50-4.60 (m, 3H), 5.04 (m, 2H),6.24-6.28 (m, 1H), 6.77 (s, 2H), 7.32 (s, 1H), 7.42 (m, 1H), 7.54-7.63(m, 2H), 7.84 (m, 1H), 8.12 (s, 1H), 8.61 (s, 1H). LCMS m/z=380.1 [MH]⁺

Example 251:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was obtained (252 mg, 73%) from4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 37), following an analogous procedure to that described inExample 250. ¹HNMR (400 MHz, DMSO-d₆) 0.86 (t, 3H), 2.45 (m, 2H), 4.10(s, 3H), 6.13 (t, 1H), 7.30 (brs, 2H), 7.48 (m, 1H), 7.55-7.62 (m, 2H),7.82 (m, 1H), 8.10 (d, 1H), 8.15 (s, 1H), 8.24 (s, 1H), 8.42 (s, 1H),8.76 (s, 1H). LCMS m/z=446.2 [MH]⁺

Example 252:7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Step 1: A suspension of4-chloro-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(Preparation 64, 0.22 mmol, 100 mg),5-bromo-4-methoxy-2-(trifluoromethyl) pyrimidine (Preparation 141, 0.29mmol, 74 mg), and Na₂CO₃ (0.88 mmol, 93 mg) in EtOH (4.5 mL) and H₂O(0.5 mL) was degassed for a few min with N₂. Pd(PPh₃)₄ (0.022 mmol, 25mg) was added and the reaction heated to 90° C. for 3 hrs. The reactionwas quenched into water and washed with EtOAc (2×). The combinedorganics were dried (MgSO₄), and evaporated to dryness in vacuo to givea yellow solid which was purified using a 24 g Isco silica gel Goldcolumn, 10-30-50% EtOAc/DCM gradient) to afford4-chloro-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidineas a white solid (62.4 mg). The compound was used without furtherpurification in Step 2.

Step 2: Aqueous NH₄OH (0.4 mL of 37%) was added to the product from Step1 (0.12 mmol, 62 mg) in dioxane (0.2 mL) in a microwave vial and thevial subjected to microwave irradiation at 130° C. for 30 min. Anadditional 0.3 mL of NH₄OH was added and the reaction re-subjected tothe same conditions: The mixture was poured into H₂O (20 mL) of waterand extracted with of EtOAc (30 mL×2). The combined organics were dried(MgSO₄) and evaporated to dryness to yield an off-white solid (47.9 mg).The resulting solid was purified by prep HPLC to afford the titlecompound (8 mg, 13.7%). LCMS m/z=486.0 [MH]⁺

Example 253:7-{[5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Step 1: To a stirred solution ofN′-(7-((5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 30, 160 mg, 0.266 mmol) in DCM (16 mL) was added TFA (0.408mL, 5.324 mmol) at rt. The reaction mixture was stirred and heated underreflux for 16 hr and evaporated to dryness under reduced pressure toaffordN′-(7-((5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(150 mg, crude) as a sticky yellow liquid which was used withoutpurification in Step 2.

Step 2: To a stirred solution of the compound from Step 1 (150 mg) inMeOH (5 mL) was added aq.NH₄OH (20 mL) at 0° C. and the reaction mixturestirred for 6 hr at 60° C. The mixture was extracted with 10% MeOH inDCM. The combined organics were dried (Na₂SO₄) and evaporated to drynessunder reduced pressure. The residue was purified by prep-TLC to affordthe title compound as an off-white solid (36 mg, 27%). ¹HNMR (400 MHz,DMSO-d₆) 3.87 (s, 3H), 5.51 (brs, 2H), 6.05 (brs, 2H), 7.08 (m, 1H),7.38-7.65 (m, 3H), 7.64 (d, 2H), 7.95 (t, 1H), 8.17 (m, 2H), 14.21 (brs,1H). LCMS m/z=417 [MH]⁺

Example 254:5-(4-Chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of5-(4-chlorophenyl)-7-(1H-pyrazol-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 38, 0.7 g, 2.16 mmol) in DMF (20 mL) was added2-bromopropane (0.32 g, 2.59 mmol) and Cs₂CO₃ (1.41 g, 4.32 mmol) andthe reaction stirred at rt for 18 hrs. The reaction was diluted withwater, extracted with EtOAc, the organic layer separated, washed withbrine, dried and evaporated. The crude product was purified by prep-HPLCto afford the title compound (0.5 g, 63%). ¹HNMR (400 MHz, DMSO-d₆) 1.35(d, 6H), 4.42 (m, 1H), 5.20 (s, 2H), 6.13 (brs, 2H), 7.41 (s, 1H),7.41-7.49 (m, 5H), 7.78 (s, 1H), 8.19 (s, 1H). LCMS m/z=367.2 [MH]⁺

Example 255:5-(4-Chlorophenyl)-7-{1-[1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Sodium azide (222 mg, 3.42 mmol) was added to a solution of cyclobutylmethyl bromide (102 mg, 0.68 mmol) in DMSO (5 mL) and the reactionstirred at 60° C. for 2 hrs. The cooled mixture was diluted with water(5 mL) and extracted with ether (3×3 mL).7-(But-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine(Preparation 77, 100 mg, 0.34 mmol), CuI (10 mg, 0.052 mmol), DIPEA (500μL, 2.86 mmol), toluene (2 mL) and t-BuOH (0.5 mL) were added and thereaction stirred at rt for 18 hrs. The mixture was evaporated underreduced pressure and the residue purified by column chromatography onsilica gel eluting with DCM: DMA (0:100 to 90:10) to afford the titlecompound as a light brown solid (29.2 mg, 10.5%). ¹HNMR (400 MHz,DMSO-d₆) 1.25 (m, 1H), 1.71-1.84 (m, 7H), 1.94-1.98 (m, 2H), 2.73 (m,1H), 4.33 (d, 2H), 6.18 (m, 3H), 7.40 (s, 1H), 7.45 (d, 2H), 7.50 (d,2H), 8.06 (s, 1H), 8.17 (s, 1H). LCMS m/z=408.18 [MH]⁺

Example 256:5-(4-Chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2-Amino-4-(4-chlorophenyl)-1-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-1H-pyrrole-3-carbonitrile(Preparation 96, 23 mg, 0.05 mmol) was dissolved in formamide (0.2 mL, 5mmol) and the reaction heated at 180° C. for 90 mins under microwaveirradiation. The cooled mixture was diluted with water (10 mL),extracted with EtOAc (2×10 mL) and the combined organic phases dried(MgSO₄), filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel eluting withMeOH:EtOAc to afford the title compound as a brown oil. ¹HNMR (400 MHz,DMSO-d₆) 2.20 (s, 6H), 6.14 (brs, 2H), 7.38 (s, 1H), 7.45 (m, 1H),7.50-7.60 (m, 6H), 7.84 (m, 1H), 8.04 (s, 1H), 8.56 (s, 1H). LCMSm/z=448.4 [MH]⁺

Example 257:5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Step 1: To a stirred solution ofN′-(7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 15, 30 mg, 0.08 mmol) in toluene:t-BuOH (1.5 mL:0.4 mL) wasadded 1-azido-2-fluoro-benzene (32.21 mg, 0.21 mmol), DIPEA (0.15 mL)and CuI (8.6 mg) at 0° C. under N₂ atmosphere. The reaction was stirredat rt for 16 hr, diluted with EtOAc, washed with water, brine, dried(Na₂SO₄) and evaporated to dryness in vacuo to affordN′-5-(4-chlorophenyl)-7-(1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamideas a brown gum (30 mg, 72.7%) which was used without any furtherpurification.

Step 2: NH₄OH (2 mL) was added to a stirred solution of the compoundfrom Step 1 (30 mg, 0.06 mmol) in MeOH (1.5 mL) in a sealed tube. Thereaction was stirred at 60° C. for 16 hr and evaporated to dryness invacuo. The residue was diluted with EtOAc, washed with water, brine,dried (Na₂SO₄) and evaporated to dryness in vacuo. The residue waspurified by prep-TLC using 50% EtOAc in hexane to afford the titlecompound as an off-white solid (19.0 mg, 51.73%). ¹HNMR (400 MHz,MeOH-d₄) 1.24 (m, 2H), 2.10 (d, 3H), 2.28 (s, 3H), 6.32 (q, 1H),7.36-7.74 (m, 6H), 7.56 (m, 1H), 8.08 (s, 1H), 8.42 (d, 1H). LCMSm/z=448.0 [MH]⁺

Example 258:5-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A stirred suspension of 5-(1-chloroethyl)-3-(2-fluorophenyl)isoxazole(Preparation 128, 50 mg, 0.204 mmol),5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,46.1 mg, 0.204) and CS₂CO₃ (166.44 mg, 0.511 mmol) in DMF (0.5 mL) washeated at 70° C. under N₂ for 5 hr. The reaction mixture was evaporatedto dryness in vacuo, diluted with EtOAc and washed with water. Theresidue was purified by column chromatography on silica gel eluting with50% EtOAc in hexane to afford the title compound as a light yellow solid(25 mg, 28%). ¹HNMR (400 MHz, MeOD-d₄) 2.01 (d, 3H), 6.33 (q, 1H), 6.77(d, 1H), 7.20-7.30 (m, 2H), 7.39 (s, 1H), 7.46-7.52 (m, 5H), 7.88 (m,1H), 8.20 (s, 1H). LCMS m/z=434 [MH]⁺

Example 259:5-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of 5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-amine (Preparation 24, 25.0 mg, 0.097 mmol) in DMF (1.0 mL)was added CS₂CO₃ (78.71 mg, 0.11 mmol) at 0° C.5-(1-Chloroethyl)-3-(2-fluorophenyl)isoxazole (Preparation 128, 23.9 mg,0.242 mmol) was added and the reaction mixture heated at 60° C. for 16hr. The reaction was diluted with EtOAc, washed with water, brine, dried(Na₂SO₄) and evaporated to dryness. The residue was purified byprep-HPLC to afford the title compound as a light brown solid (10 mg,23%). ¹HNMR (400 MHz, MeOH-d₄) 2.08 (d, 3H), 2.26 (s, 3H), 6.33 (q, 1H),6.81 (d, 1H), 7.23-7.30 (m, 2H), 7.39 (d, 2H), 7.50 (d, 2H), 7.78-7.92(m, 2H), 8.09 (s, 1H). LCMS m/z=448 [MH]⁺

Example 260:5-(4-Chlorophenyl)-7-{1-[3-(2-methoxyphenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

CS₂CO₃ (267 mg, 0.82 mmol) was added to a stirred solution of5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,80 mg, 0.328 mmol) and 5-(1-chloroethyl)-3-(2-methoxyphenyl)isoxazole(Preparation 124, 93 mg, 0.393 mmol) in DMF (1 mL) at rt and theresulting mixture heated at 60° C. for 4 hr. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (2×20 mL). Thecombined extracts were washed with water, brine, dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to afford the title compound as an off white solid (12.5mg, 8.55%). ¹HNMR (400 MHz, MeOH-d₄) 1.99 (d, 3H), 3.87 (s, 3H), 6.32(q, 1H), 6.80 (s, 1H), 7.00 (t, 1H), 7.11 (d, 1H), 7.36 (s, 1H),7.40-7.51 9m, 5H), 7.73 (dd, 1H). LCMS m/z=446 [MH]⁺

Example 261:5-(4-Chlorophenyl)-7-{1-[3-(3-methoxyphenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off white solid (28 mg, 17%) in ananalogous manner to Example 260 using of5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,105 mg, 0.443 mmol) and 5-(1-chloroethyl)-3-(3-methoxyphenyl)isoxazole(Preparation 126, 90 mg, 0.369 mmol). ¹HNMR (400 MHz, MeOH-d₄) 1.99 (s,3H), 3.83 (s, 3H), 6.31 (q, 1H), 6.82 (s, 1H), 7.02 (m, 1H), 7.33-7.40(m, 4H), 7.45-7.53 (m, 4H), 8.20 (s, 1H). LCMS m/z=446 [MH]⁺

Example 262:5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off white solid (23 mg, 27%) in ananalogous manner to Example 260 using5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,50 mg, 0.204 mmol) and 4-(chloromethyl)-1-(2-fluorophenyl)-1H-pyrazole(Preparation 98, 43 mg, 0.204 mmol). ¹HNMR (400 MHz, MeOH-d₄) 5.39 (s,2H), 7.25-7.44 (m, 4H), 7.45 (m, 4H), 7.73 (t, 1H), 7.76 (s, 1H), 8.15(d, 1H), 8.21 (s, 1H). LCMS m/z=419 [MH]⁺

Example 263:5-(4-Chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off white solid (13 mg, 13%) in ananalogous manner to Example 260 using5-(4-chlorophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine (Preparation 80,58 mg, 0.24 mmol) and 5-chloromethyl-2-(2-fluorophenyl)-1H-imidazole(Preparation 105, 50 mg, 0.24 mmol). ¹HNMR (400 MHz, MeOD-d₄) 5.41 (m,1H), 7.14-7.33 (m, 4H), 7.38-7.50 (m, 5H), 7.95 (m, 1H), 8.20 (s, 1H).LCMS m/z=419 [MH]⁺

Example 264:5-(4-Chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as a pale yellow solid (25 mg, 5.1%) inan analogous manner to Example 260 using5-(4-chlorophenyl)-7H-pyrrolo[2,3-d] pyrimidine-amine (Preparation 80,300 mg, 1.23 mmol) and 5-(chloromethyl)-2-phenyl-1H-imidazole(Preparation 106, 473 mg, 2.45 mmol). ¹HNMR (400 MHz, MeOH-d4) 5.39 (m,2H), 7.13 (s, 1H), 7.28 (s, 1H), 7.34-7.49 (m, 7H), 7.82 (s, 1H), 7.84(s, 1H), 8.20 (s, 1H). LCMS m/z=401 [MH]⁺

Example 265:5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-imidazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off-white solid (13.2 mg, 10%) inan analogous manner to Example 260 using5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,80 mg, 1.23 mmol) and 4-(chloromethyl)-1-(2-fluorophenyl)-1H-imidazole(Preparation 108, 76 mg, 0.36 mmol). ¹HNMR (400 MHz, DMSO-d₆) 5.32 (s,2H), 6.13 (brs, 2H), 7.30-7.54 (m, 8H), 7.55 (s, 1H), 7.62 (t, 1H), 8.00(s, 1H), 8.18 (s, 1H). LCMS m/z=419 [MH]⁺

Example 266:5-(4-Chlorophenyl)-7-{1-[3-(2-methylphenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off-white solid (40 mg, 23%) in ananalogous manner to Example 260 using5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,100 mg, 0.41 mmol) and 5-(1-chloroethyl)-3-(o-tolyl)isoxazole(Preparation 132, 109 mg, 0.49 mmol). ¹HNMR (400 MHz, MeOH-d₄) 2.00 (d,3H), 2.41 (s, 3H), 6.34 (q, 1H), 6.62 (s, 1H), 7.22-7.36 (m, 3H), 7.39(s, 1H), 7.44-7.52 (m, 5H), 8.20 (s, 1H). LCMS m/z=430 [MH]⁺

Example 267:5-(4-Chlorophenyl)-7-{1-[3-(3-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared as an off-white solid (40 mg, 23%) in ananalogous manner to Example 260 using of5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,100 mg, 0.41 mmol) and 5-(1-chloroethyl)-3-(3-fluorophenyl)isoxazole(Preparation 134, 110 mg, 0.49 mmol). ¹HNMR (400 MHz, MeOD-d₄) 2.00 (d,3H), 6.31 (q, 1H), 6.85 (s, 1H), 7.22 (m, 1H), 7.37 (s, 1H), 7.43-7.52(m, 5H), 7.56 (m, 1H), 7.64 (m, 1H), 8.20 (s, 1H). LCMS m/z=434 [MH]⁺

Example 268:7-{[1-(2-Fluorophenyl)-1H-pyrazol-3-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a stirred solution of5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 22, 115 mg, 0.47 mmol) in DMF (8 mL) was added CS₂CO₃(387.3 mg, 1.2 mmol) and 3-chloromethyl-1-(2-fluorophenyl)-1H-pyrazole(110 mg, 0.52 mmol) at rt. The resulting mixture was stirred at rt for16 hr, diluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andevaporated to dryness in vacuo. The residue was purified by prep-TLC(50% EtOAc-Hexane) to afford the title compound as an off-white solid(12 mg, 6%). ¹HNMR (400 MHz, CDCl₃) 3.91 (s, 3H), 5.45 (s, 2H), 6.37 (d,1H), 6.94 (dd, 1H), 7.13 (s, 1H), 7.20-7.30 (m, 3H), 7.54 (m, 1H), 7.78(m, 1H), 7.85 (t, 1H), 8.10 (m, 1H), 8.25 (s, 1H). LCMS m/z=416 [MH]⁺

Example 269:5-(4-Chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

NaH (60% dispersion in oil, 15 mg, 0.368 mmol) was added to5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80,100 mg, 0.409 mmol) in DMF (1 mL) at 0° C., then5-(chloromethyl)-3-cyclohexylisoxazole (82 mg, 0.409 mmol) was added andthe reaction stirred at 60° C. in a sealed tube for 3 hr. The reactionwas quenched with H₂O and extracted with EtOAc. The combined organicswere washed (H₂O), dried (Na₂SO₄) and evaporated to dryness in vacuo.The residue was purified by column chromatography on silica gel elutingwith 100% DCM to 95:5 DCM:MeOH to afford the title compound as a palebrown solid (96 mg, 57%). Mp: 173-175° C. ¹HNMR (400 MHz, DMSO-d₆)1.21-1.38 (m, 5H), 1.63-1.72 (m, 3H), 1.81-1.86 (m, 2H), 2.62-2.68 (m,1H), 5.53 (s, 2H), 6.23 (brs, 2H), 6.32 (s, 1H), 7.46-7.54 (m, 5H), 8.19(s, 1H). LCMS m/z=408.3 [MH⁺]

Example 270:7-({1-[4-(Difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

1-Bromo-4-(difluoromethyl)benzene (625 μmol) was added to5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Preparation 22; 125 μ□mol, 40 mg) in a reaction vial. Anhydrous Cs₂CO₃(312.5 μmol, 105 mg) was added followed by trans N,N′dimethylcyclohexane1,2-diamine (62.5 μmol 10 μL) and CuI (25 μmol, 4.8 mg) under Ar. Thereaction vial was heated with stirring at 110° C. for 30 hrs. Thereaction mixture was diluted with DMSO (1 mL) and purified by prep-HPLCto afford the title compound. LCMS RT=1.48 minutes; LCMS m/z=448.37[MH]⁺

Example 271:7-{1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution ofN′-(7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 4, 300 mg, 0.56 mmol), MeOH (10 mL) and addedNH₃.H₂O (20 mL) was stirred at 100° C. in a sealed tube overnight. Thecooled mixture was diluted (EtOAc), washed with brine and the organiclayer collected, dried and evaporated. The crude was purified by prepHPLC to afford the title compound (120 mg, 44%). ¹HNMR (DMSO-d₆) 0.83(t, 3H), 2.27-2.36 (m, 2H), 5.92 (m, 1H), 6.64 (s, 2H), 7.31 (m, 1H),7.34-7.43 (m, 2H), 7.74 (m, 1H), 7.87 (s, 1H), 7.96 (s, 1H), 8.25 (s,1H), 8.30 9s, 1H), 9.06 (s, 2H). LCMS m/z=483.1 [MH]⁺

Example 272:5-(2-Methoxypyridin-3-yl)-7-[(5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared using an analogous method to Example 271as an off-white solid (31 mg, 28%), usingN′-(5-(2-methoxypyridin-3-yl)-7-((5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 31). ¹HNMR(400 MHz, DMSO-d₆) 3.90 (s, 3H), 5.52 (s, 2H), 5.73 (s, 2H), 7.06 (dd,1H), 7.35 (s, 1H), 7.46 (m, 3H), 7.64 (d, 1H), 7.97 (m, 2H), 8.17 (s,2H), 13.98 (brs, 1H). LCMS m/z=399 [MH]⁺

Example 273:7-{1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture ofN′-(7-(1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 8, 900 mg, 1.67 mmol) in dioxane (20 mL) and NH₃.H₂O (30mL) was stirred at 90° C. for 16 hrs. The solvent was removed in vacuoand the residue was purified by trituration with MeOH to afford thetitle compound (610 mg, 75%) as a brown solid. LCMS m/z=484.0 [MH]⁺

Example 274:7-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A sealed tube was charged withN′-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 5, 650 mg, 1.17 mmol), dioxane (10 mL) and NH₃.H₂O (15 mL).The sealed tube was stirred at 90° C. for 16 hrs, cooled to rt andevaporated to dryness in vacuo. The residue was purified by prep-HPLCeluting with MeCN in water (0.1% TFA) from 40% to 50% in 8 minutes togive the title compound as a brown solid (420 mg, 71%). ¹HNMR (400 MHz,DMSO-d₆): 0.86 (m, 3H), 2.35 (m, 2H), 5.96 (t, 1H), 7.25 (m, 1H), 7.53(m, 1H), 7.75 (m, 1H), 7.80 (s, 1H), 8.10-8.40 (m, 4H), 8.54 (s, 1H),9.13 (s, 2H). LCMS m/z=501.5 [MH]⁺

Example 275:7-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared (300 mg, 83%) in an analogous manner toExample 274 usingN′-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 3, 0.4 g, 0.74 mmol). LCMS m/z=487.0 [MH]⁺

Example 276:7-{1-[2-(2,4-Difluorophenyl)-2H-imidazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared (220 mg, 54%) in an analogous manner toExample 274, usingN′-(7-(1-(2-(2,4-difluorophenyl)-2H-imidazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 7, 0.45 g, 0.81 mmol). LCMS m/z=501.0 [MH⁺]

Example 277:7-(1-(1-(2-Fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared (400 mg, 67%) in an analogous manner toExample 274 usingN′-(7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 2, 666 mg, 1.28 mmol). LCMS m/z=469.1 [MH]⁺

Example 278:7-{[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared (54.5 mg, 28%) in an analogous manner toExample 274 usingN′-(7-{[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 10, 220 mg, 0.44 mmol). ¹HNMR (400 MHz,DMSO-d₆): 2.39 (s, 3H), 3.91 (s, 3H), 5.59 (s, 2H), 5.86 (brs, 2H), 6.93(d, 1H), 7.30 (t, 1H), 7.63 (m, 2H), 7.85 (t, 1H), 8.13 (m, 2H), 8.54(s, 1H). LCMS m/z=449.2 [MH]⁺

Example 279:7-{[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compound was prepared (600 mg, 89%) in an analogous manner toExample 274 usingN′-(7-((1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide(Preparation 1, 750 mg, 1.422 mmol). ¹HNMR (400 MHz, DMSO-d₆): 5.38 (s,2H), 6.64 (br s, 2H), 7.23 (t, 1H), 7.52 (t, 1H), 7.70-7.80 (m, 3H),8.26 (s, 2H), 9.04 (s, 1H). LCMS m/z=473.1 [MH]⁺

The following compounds were prepared by analogy to the methodspreviously described:

Example 280:5-(4-Chlorophenyl)-7-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 0.71 (m, 2H), 0.96 (m, 2H), 1.94 (m, 1H), 5.50(s, 2H), 6.15 (s, 1H), 6.22 (brs, 2H), 7.43 (s, 1H), 7.44 (d, 2H), 7.52(d, 2H), 8.10 (s, 1H). LCMS m/z=366.0 [MH]⁺

Example 281:5-(4-Chlorophenyl)-7-[(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, CDCl₃): 1.71-1.78 (m, 2H), 1.85-1.89 (m, 2H), 1.97-2.04(m, 2H), 2.19-2.25 (m, 2H), 4.84-4.90 (m, 1H), 5.10 (brs, 2H), 5.11 (s,2H), 7.18 (s, 1H), 7.38-7.43 (m, 4H), 7.58 (s, 1H), 8.37 (s, 1H). LCMSm/z=394.0 [MH]⁺

Example 282:5-(4-Chlorophenyl)-7-[(4-phenyl-1H-imidazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆): 2.36 (s, 3H), 5.54 (s, 2H), 6.17 (brs, 2H),7.37 (s, 2H), 7.46-7.52 (m, 5H), 7.75 (s, 2H), 8.20 (s, 1H), 8.75 (s,1H). LCMS m/z=416.0 [MH]⁺

Example 283:5-(4-Chlorophenyl)-7-([3-(propan-2-yl)-1,2-oxazol-5-yl]methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, CDCl₃): 1.24 (d, 6H), 3.02 (m, 1H), 5.10 (m, 1H), 5.49(s, 2H), 6.07 (s, 1H), 7.07 (s, 1H), 7.43 (m, 4H), 8.36 (s, 1H). LCMSm/z=366.1 [MH]⁺

Example 284:5-(4-Chlorophenyl)-7-[(5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 0.85 (m, 2H), 0.97 (m, 2H), 1.98 (m, 1H), 5.31(s, 2H), 6.16 (brs, 2H), 7.31 (s, 1H), 7.46 (d, 2H), 7.49 (d, 2H), 8.15(s, 1H), 13.47 (s, 1H). LCMS m/z=366.0 [MH]⁺

Example 285:5-(4-Chlorophenyl)-7-{[5-(2-fluorophenyl)-1H-imidazol-2-yl]methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, MeOD-d₄) 5.70 (s, 2H), 7.10-7.24 (m, 4H), 7.34 (s, 1H),7.44 (m, 4H), 7.88 (m, 1H), 8.42 (s, 1H). LCMS m/z=419.0 [MH]⁺

Example 286:7-{[1-(2,6-Difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 3.86 (s, 3H), 5.33 (s, 2H), 6.03 (br s, 2H),7.07 (m, 1H), 7.34 (m, 2H), 7.42 (s, 1H), 7.54-7.60 (m, 1H), 7.64 (m,1H), 7.84 (s, 1H), 8.16 (m, 3H). LCMS m/z=491.2 [MH]⁺

Example 287:5-(4-Chlorophenyl)-7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, MeOD-d₄): 2.03 (d, 3H), 6.36 (q, 1H), 7.38 (s, 1H),7.44-7.49 (m, 4H), 7.60 (m, 1H), 7.92-7.97 (m, 1H), 8.20 (d, 1H), 8.41(m, 1H), 8.58 (s, 1H). LCMS m/z=435.0 [MH]⁺

Example 288:[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 0.67 (m, 2H), 0.80 (m, 2H), 1.94 (d, 3H), 3.87(m, 1H), 6.14 (brs, 2H), 6.32 (q, 1H), 7.14 (m, 2H), 7.40 (m, 3H), 7.71(m, 1H), 8.15 (m, 1H), 8.19 (s, 1H), 8.48 (d, 1H), 8.74 (s, 1H). LCMSm/z=457.0 [MH]⁺

Example 289:5-Cyclopropyl-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 0.63 (m, 2H), 0.91 (m, 2H), 2.00 (m, 1H), 5.46(s, 2H), 6.96 (s, 1H), 7.35-7.42 (m, 2H), 7.54 (m, 1H), 7.78 (m, 1H),8.09 (s, 1H), 8.30 (s, 1H). LCMS m/z=349.9 [MH]⁺

Example 290:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(methoxymethyl)cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, MeOD-d₄) 0.86 (m, 1H), 1.08 (m, 1H), 1.16-1.26 (m, 1H),1.86 (m, 1H), 2.86 (dd, 1H), 3.30 (s, 3H), 3.88 (m, 1H), 5.48 (s, 2H),6.96 (s, 1H), 7.35-7.42 (m, 2H), 7.53 (m, 1H), 7.78 (m, 1H), 8.06 (s,1H), 8.30 (s, 1H). LCMS m/z=394.2 [MH]⁺

Example 292:[3-(4-Amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)azetidin-1-yl](cyclopropyl)methanone;¹HNMR (400 MHz, DMSO-de) 0.72 (m, 4H), 1.58 (m, 1H), 3.86 (m, 1H), 4.21(m, 1H), 4.27 (m, 2H), 4.78 (m, 1H), 5.49 (s, 2H), 6.55 (s, 2H), 7.40(m, 2H), 7.54-7.63 (m, 2H), 7.72 (m, 1H), 8.12 (s, 1H), 8.55 (s, 1H).LCMS m/z=433.0 [MH]⁺

Example 293:5-{1-[(Cyclopropylmethyl)sulfenyl]azetidin-3-yl}-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;_¹HNMR(400 MHz, DMSO-d₆) 0.38 (m, 2H), 0.62 (m, 2H), 1.08 (m, 1H), 1.32 (m,1H), 3.17 (m, 1H), 3.98 (m, 2H), 4.30 (m, 3H), 5.54 (s, 2H), 6.66 (brs,2H), 7.42-7.67 (m, 4H), 7.86 (m, 1H), 8.14 (s, 1H), 8.60 (s, 1H). LCMSm/z=483.1 [MH]⁺

Example 294:5-Cyclobutyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; ¹HNMR (400 MHz, DMSO-d₆) 1.91-1.95 (m, 1H), 2.00-2.20 (m,8H), 2.33-2.42 (m, 2H), 5.07 (s, 2H), 6.31 (m, 1H), 7.23-7.31 (m, 2H),7.41 (m, 1H), 7.92 (m, 2H), 8.26 (s, 1H)._LCMS m/z=378.2 [MH]⁺; RT [SFCMethod A8]=4.963 mins

Example 295:5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, CDCl₃) 0.69 (m, 2H), 0.91 (m, 2H), 1.68 (m, 2H),1.89-1.94 (m, 3H), 5.46 (s, 2H), 6.86 (s, 1H), 7.17-7.26 (m, 2H), 7.36(m, 1H), 7.50 (s, 1H), 7.80 (m, 1H), 8.29 (s, 1H). LCMS m/z=376.0 [MH]⁺

Example 296:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 4.15 (s, 3H), 5.74 (s, 2H), 7.42 (m, 1H),7.52-7.64 (m, 2H), 7.79 (m, 1H), 8.20 (d, 1H), 8.32 (d, 1H), 8.42 (s,1H), 8.65 (d, 1H), 8.70 (d, 1H), 10.78 (brs, 1H). LCMS m/z=418.2 [MH]⁺

Example 297:7-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 0.45 (m, 1H), 0.58 (m, 2H), 0.73 (m, 1H), 1.97(m, 1H), 3.87 (s, 3H), 5.45 (d, 1H), 6.06 (brs, 2H), 7.08 (m, 1H), 7.44(m, 1H), 7.54-6.62 (m, 3H), 7.66 (m, 1H), 7.84 (m, 1H), 8.13 (s, 1H),8.18 (m, 1H), 8.77 (s, 1H). LCMS m/z=457.0 [MH]⁺

Example 298:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;_¹HNMR (400 MHz, CDCl₃) 1.80 (m, 2H), 1.96 (m, 2H), 3.98 (s, 3H), 5.04(brs, 2H), 6.99 (m, 1H), 7.18-7.28 (m, 3H), 7.34-7.40 (m, 1H), 7.62 (m,1H), 7.66 (d, 1H), 7.82 (m, 1H), 8.19 (m, 1H), 8.37 (s, 1H). LCMSm/z=443.0 [MH]⁺

Example 299:5-(1,3-Benzoxazol-7-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 5.63 (s, 2H), 6.17 (brs, 2H), 7.39-7.61 (m,5H), 7.67 (s, 1H), 7.76 (d, 1H), 7.81 (m, 1H), 8.23 (s, 1H), 8.63 (m,1H), 8.78 (s, 1H). LCMS m/z=427.0 [MH]⁺

Example 300: (−)7-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using SFC Method D4; ¹HNMR (400 MHz, DMSO-d₆)0.45 (m, 1H), 0.58 (m, 2H), 0.71 (m, 1H), 1.96 (m, 1H), 3.94 (s, 3H),5.46 (d, 1H), 6.29 (s, 2H), 7.43 (m, 1H), 7.56-7.63 (m, 3H), 7.84 (m,1H), 8.13 (s, 1H), 8.43 (s, 1H), 8.76 (s, 2H). LCMS m/z=458.1 [MH]⁺; RT[SFC Method D2]=9.322 min; [α]_(D) MeOH=−19.9°.

Example 301:7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 5.65 (s, 2H), 7.40-7.67 (m, 5H), 7.86 (m, 1H),8.12 (d, 1H), 8.18 (s, 1H), 8.22 (s, 1H), 8.66 (s, 1H), 9.02 (brs, 1H).LCMS m/z=377.1 [MH]⁺

Example 302:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, CDCl₃) 0.95 (t, 3H), 2.38-2.48 (m, 1H), 2.50-2.60 (m,1H), 4.03 (s, 3H), 4.92 (s, 2H), 6.13 (m, 1H), 7.25-7.32 (m, 2H)7.38-7.43 (m, 2H), 7.93 (m, 1H), 8.09 (s, 1H), 8.47 (s, 1H), 8.74 (s,1H). LCMS m/z=460.2 [MH]⁺

Example 303: (+)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; Separated using SFC Method B1; ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.28-2.36 (m, 2H), 2.48 (s, 3H), 3.93 (s, 3H), 6.08 (m,1H), 6.22 (brs, 2H), 7.45 (m, 2H), 7.68 (m, 2H), 7.83 (m, 1H), 8.40 (s,1H), 8.74 (m, 2H). LCMS m/z=460.3 [MH]⁺; RT [SFC method B2]=5.064 min;[α]_(D) MeOH=+4.4°

Example 304: (−)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using SFC Method B1; ¹HNMR (400 MHz, DMSO-d₆)0.84 (t, 3H), 2.28-2.36 (m, 2H), 2.48 (s, 3H), 3.93 (s, 3H), 6.08 (m,1H), 6.22 (brs, 2H), 7.45 (m, 2H), 7.55-7.64 (m, 2H), 7.83 (m, 1H), 8.40(s, 1H), 8.72 (s, 1H), 8.75 (s, 1H). LCMS m/z=460.3 [MH]⁺; RT [SFCmethod B2]=5.884 min

Example 305: (−)7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; Separated using SFC method A10; ¹HNMR (400 MHz, DMSO-d₆)0.87 (t, 3H), 2.36 (m, 2H), 3.95 (s, 3H), 6.10 (t, 1H), 6.32 (brs, 2H),7.45 (m, 1H), 7.53 (s, 1H), 7.65-7.73 (m, 2H), 8.18 (s, 1H), 8.43 (s,1H), 8.76 (s, 2H). LCMS m/z=464.1 [MH]⁺; RT [SFC Method A2]=4.106 min;[α]_(D) MeOH=−25.2°

Example 306: (+) 7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using SFC Method A10; ¹HNMR (400 MHz, DMSO-d₆)0.87 (t, 3H), 2.36 (m, 2H), 3.95 (s, 3H), 6.10 (t, 1H), 6.32 (brs, 2H),7.45 (m, 1H), 7.55 (s, 1H), 7.65-7.73 (m, 2H), 8.18 (s, 1H), 8.43 (s,1H), 8.76 (s, 2H). LCMS m/z=464.1 [MH]⁺; RT [SFC Method A2]=4.455 min;[α]_(D) MeOH=+27.3°

Example 307: (+)7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; Separated using SFC Method F1; ¹HNMR (400 MHz, DMSO-d₆)0.87 (t, 3H), 2.36 (m, 2H), 3.95 (s, 3H), 6.10 (t, 1H), 6.35 (brs, 2H),7.50 (m, 1H), 7.56 (s, 1H), 7.67 (m, 1H), 7.84 (m, 1H), 8.18 (s, 1H),8.43 (s, 1H), 8.76 (s, 2H). LCMS m/z=464.1 [MH]⁺; RT [SFC MethodF2]=7.170 min; [α]_(D) MeOH=+25.9°

Example 308: (−)7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using SFC Method F1; ¹HNMR (400 MHz, DMSO-d₆)0.87 (t, 3H), 2.36 (m, 2H), 3.95 (s, 3H), 6.10 (t, 1H), 6.35 (brs, 2H),7.50 (m, 1H), 7.56 (s, 1H), 7.67 (m, 1H), 7.84 (m, 1H), 8.18 (s, 1H),8.43 (s, 1H), 8.76 (s, 2H). LCMS m/z=464.1 [MH]⁺; RT [SFC MethodF2]=7.535 min; [α]_(D) MeOH=−21.9°

Example 309:7-{1-[1-(6-Methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; Separated using method HPLC Method C30; ¹HNMR (400 MHz,DMSO-d₆) 0.87 (t, 3H), 2.34-2.40 (m, 2H), 3.92 (s, 3H), 6.11 (m, 1H),7.00-7.06 (m, 3H), 7.90 (s, 1H), 8.20-8.35 (m, 2H), 8.67 (s, 1H), 8.88(s, 1H), 9.08 (s, 2H). LCMS m/z=497.2 [MH]⁺; RT [HPLC method C10]=2.339min

Example 310:7-{1-[1-(6-Methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using method HPLC Method C30; ¹HNMR (400 MHz,DMSO-d₆) 0.86 (t, 3H), 2.35-2.41 (m, 2H), 3.92 (s, 3H), 6.10 (m, 1H),6.70 (brs, 2H), 7.05 (m, 1H), 7.86 (s, 1H), 8.18 (m, 1H), 8.26 (s, 1H),8.67 (s, 1H), 8.90 (s, 1H), 9.07 (s, 2H). LCMS m/z=497.2 [MH]⁺; RT [HPLCMethod C10]=2.882 min

Example 311:7-{1-[1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1; Separated using method HPLC Method G3; ¹HNMR (400 MHz,DMSO-d₆) 0.86 (t, 3H), 2.37-2.41 (m, 2H), 6.10 (t, 1H), 6.67 (brs, 2H),7.43 (m, 1H), 7.76 (m, 2H), 7.82 (s, 1H), 8.25 (s, 1H), 9.00 (s, 1H),9.06 (s, 2H). LCMS m/z=502.1 [MH]⁺

Example 312:7-{1-[1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using HPLC Method G3; ¹HNMR (400 MHz, DMSO-d₆)0.86 (t, 3H), 2.33-2.41 (m, 2H), 6.10 (t, 1H), 6.67 (br s, 2H), 7.43 (m,1H), 7.76 (m, 2H), 7.82 (s, 1H), 8.25 (s, 1H), 9.00 (s, 1H), 9.06 (s,2H). LCMS m/z=502.1 [MH]⁺

Example 313:5-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using HPLC Method C22A; ¹HNMR (400 MHz, DMSO-d₆)0.85 (t, 3H), 2.33-2.41 (m, 2H), 6.09 (t, 1H), 6.77 (brs, 2H), 6.88-7.15(dd, 1H), 7.67 (m, 1H), 7.85 (m, 2H), 8.10 (m, 1H), 8.28 (s, 1H), 8.93(s, 1H), 9.00 (s, 1H). LCMS m/z=484.1 [MH]⁺; RT [HPLC Method C1]=4.154min.

Example 314:7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2-methoxyethyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, DMSO-d₆) 3.32 (s, 3H), 3.85 (s, 3H), 4.05 (m, 1H), 4.24(m, 1H), 6.06 (br s, 2H), 6.42 (m, 1H), 7.08 (m, 1H), 7.42 (m, 1H), 7.50(s, 1H), 7.54-7.66 (m, 3H), 7.83 (m, 1H), 8.16 (m, 2H), 8.74 (s, 1H).LCMS m/z=461.3 [MH]⁺

Example 315:7-{[1H-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl](oxetan-3-yl)methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, MeOD-d₄) 4.05 (s, 3H), 4.32 (m, 1H), 4.54 (m, 1H), 4.58(m, 1H), 4.64 (m, 1H), 4.91 (m, 1H), 6.70 (d, 1H), 7.39-7.48 (m, 3H),7.55 (m, 1H), 7.82 (m, 1H), 8.25 (s, 1H), 8.46 (s, 2H), 8.75 (s, 1H).LCMS m/z=474.2 [MH]⁺

Example 316: (+)5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2; Separated using SFC method C3; ¹HNMR (400 MHz, DMSO-d₆)0.54 (m, 2H), 0.76-0.85 (m, 6H), 2.20-2.33 (m, 2H), 5.95 (m, 1H), 6.60(br s, 2H), 7.02 (s, 1H), 7.42 (m, 1H), 7.52-7.62 (m, 2H), 7.81 (m, 1H),8.05 (s, 1H), 8.61 (s, 1H). LCMS m/z=378.4 [MH]⁺; RT [SFC MethodC2]=6.081 min; [α]_(D) MeOH=+29.5°

Example 317:5-Cyclopropyl-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, CDCl₃) 0.65 (m, 2H), 0.88 (m, 2H), 1.91 (m, 1H), 5.24(s, 2H), 5.45 (s, 2H), 6.70 (s, 1H), 7.17-7.25 (m, 3H), 7.66 (s, 1H),7.82 (m, 1H), 7.96 (s, 1H), 8.29 (s, 1H). LCMS m/z=349.2 [MH]⁺

Example 318:5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;¹HNMR (400 MHz, MeOD-d₄) 2.00 (d, 3H), 2.98 (s, 3H), 6.34 (m, 1H), 7.30(s, 1H), 7.36-7.47 (m, 6H), 7.54 (m, 1H), 7.81 (m, 1H), 8.23 (s, 1H),8.38 (s, 1H). LCMS m/z=447.8 [MH]⁺

Example 319:6-Bromo-5-(4-chlorophenyl)-7-{H-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;LCMS m/z=500.0 [MH]⁺

Example 320:4-Amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-(1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,enantiomer 1; Separated using HPLC method Q1; ¹HNMR (400 MHz, CDCl₃):0.77 (m, 4H), 2.12 (d, 3H), 4.20 (m, 1H), 5.31 (br s, 2H), 6.58 (m, 1H),6.85 (d, 1H), 6.98 (m, 1H), 7.71 (d, 1H), 7.85 (m, 1H), 8.11 (s, 1H),8.34 (s, 1H), 8.38 (s, 1H). LCMS m/z=500.1 [MH]⁺

Example 321:4-Amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,enantiomer 2; Separated using HPLC method Q1; ¹HNMR (400 MHz, DMSO-d₆)0.79 (m, 2H), 0.86 (m, 1H), 2.10 (d, 3H), 4.33 (m, 1H), 6.52 (q, 1H),7.10 (d, 1H), 7.41 (m, 1H), 7.71 (m, 1H), 7.90 (m, 2H), 8.38 (s, 2H),8.80 (s, 1H). LCMS m/z=500.1 [MH]⁺

Example 322:4-Amino-7-{1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,enantiomer 1; Separated using method HPLC C34; ¹HNMR (400 MHz, DMSO-d₆)0.93 (m, 3H), 2.50-2.57 (m, 2H), 6.26 (t, 1H), 7.20 (brs, 2H), 7.68 (m,1H), 7.84 (m, 1H), 8.09 (m, 1H), 8.38 (s, 1H), 9.02 (s, 1H), 9.22 (s,2H). LCMS m/z=527.2 [MH]⁺; RT [HPLC method C11]=5.864 min

X-Ray Crystallography Methods

The following methods were used to obtain X-Ray crystallography data forseveral compounds.

Single Crystal X-Ray Analysis for Example 27.

Data collection was performed en a Bruker APEX diffractometer at roomtemperature. Data collection consisted cf omega and phi scans. Thestructure was solved by direct methods using SHELX software suite in theMonoclinic class space group C2/c. The structure was subsequentlyrefined by the full-matrix least squares method. All non-hydrogen atomswere found and refined using anisotropic displacement parameters.

The hydrogen atoms located on nitrogen were found from the Fourierdifference map and refined with distances restrained. The remaininghydrogen atoms were placed in calculated positions and were allowed toride on their carrier atoms. The final refinement included isotropicdisplacement parameters for all hydrogen atoms. CF3 group is disorderedand modeled with two occupancies. The final R-index was 3.8%. A finaldifference Fourier revealed no missing or misplaced electron density.Pertinent crystal, data collection and refinement are summarized inTable XRAY-EX27.

TABLE XRAY-EX27. Crystal data and structure refinement for Example 27.Empirical formula C22 H13 N9 F4 Formula weight 479.41 Temperature 296(2)K Wavelength 1.54178 Å Crystal system Monoclinic Space group C2/c Unitcell dimensions a = 40.9109(10) Å □ = 90°. b = 6.1608(2) Å □ =116.502(3)°. c = 18.5613(5) Å □ = 90°. Volume 4186.7(2) Å³ Z 8 Density(calculated) 1.521 Mg/m³ Goodness-of-fit on F² 1.034 Final R indices[I > R1 = 0.0383, wR2 = 0.0996 2sigma(I)] R indices (all data) R1 =0.0484, wR2 = 0.1062

Single Crystal X-Ray Analysis for Example 161.

The compound of Example 161 was found to be7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

Data collection was performed on a Bruker APEX diffractometer at roomtemperature. Data collection consisted of omega and phi scans. Thestructure was solved by direct methods using SHELX software suite in thespace group P2₁. The structure was subsequently refined by thefull-matrix least squares method. All non-hydrogen atoms were found andrefined using anisotropic displacement parameters. The hydrogen atomslocated on nitrogen were found from the Fourier difference map andrefined with distances restrained. The remaining hydrogen atoms wereplaced in calculated positions and were allowed to ride on their carrieratoms. The final refinement included isotropic displacement parametersfor all hydrogen atoms. Molecules in asymmetric unit arranged in apseudo-symmetry relationship. Both molecules in the asymmetric unit havethe same chirality. Analysis of the absolute structure using likelihoodmethods (Hooft 2008) was performed using PLATON (Spek 2010). The samplewas assumed to be enantiopure; the results indicate that the absolutestructure has been correctly assigned. The final R-index was 4.9%. Afinal difference Fourier revealed no missing or misplaced electrondensity. Pertinent crystal, data collection and refinement aresummarized in Table XRAY-EX161.

TABLE XRAY-EX161. Crystal data and structure refinement for Example 161.Empirical formula C22 H16 F5 N9 Formula weight 501.44 Temperature 296(2)K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unitcell dimensions a = 16.0097(8) Å □□ = 90°. b = 7.8827(5) Å □□ =102.096(3)°. c = 17.6077(10) Å □ = 90°. Volume 2172.8(2) Å³ Z 4 Density(calculated) 1.533 Mg/m³ Goodness-of-fit on F² 1.039 Final R indices[I > R1 = 0.0491, wR2 = 0.1256 2sigma(I)] R indices (all data) R1 =0.0657, wR2 = 0.1381

Single Crystal X-Ray Analysis for Example 162.

The compound of Example 162 was found to be7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

Data collection was performed on a Bruker APEX diffractometer at roomtemperature. Data collection consisted of omega and phi scans. Thestructure was solved by direct methods using SHELX software suite in theMonoclinic class space group P2₁. The structure was subsequently refinedby the full-matrix least squares method. All non-hydrogen atoms werefound and refined using anisotropic displacement parameters. Thehydrogen atoms located on nitrogen were found from the Fourierdifference map and refined with distances restrained. The remaininghydrogen atoms were placed in calculated positions and were allowed toride on their carrier atoms. The final refinement included isotropicdisplacement parameters for all hydrogen atoms. Analysis of the absolutestructure using likelihood methods (Hooft 2008) was performed usingPLATON (Spek2010). Assuming the sample submitted is enantiopure, theresults indicate that the absolute structure has been correctlyassigned. Absolute configuration confirmed as opposite to other singleenantiomer resolved. The final R-index was 5.8%. A final differenceFourier revealed no missing or misplaced electron density. Pertinentcrystal, data collection and refinement are summarized in TableXRAY-EX162.

TABLE XRAY-EX162. Crystal data and structure refinement for Example 162.Empirical formula C22 H16 F5 N9 Formula weight 501.44 Temperature 296(2)K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unitcell dimensions a = 16.0163(6) Å □ = 90°. b = 7.8766(3) Å □ =102.117(2)°. c = 17.6201(8) Å □ = 90°. Volume 2173.32(15) Å³ Z 4 Density(calculated) 1.533 Mg/m³ Goodness-of-fit on F² 1.026 Final R indices[I > 2sigma(I)] R1 = 0.0576, wR2 = 0.1374 R indices (all data) R1 =0.0758, wR2 = 0.1487

SOFTWARE AND REFERENCES

-   SHELXTL, Version 5.1, Bruker AXS, 1997.-   PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13.-   MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P.    Shields, R. Taylor, M. Towler and J. van de Streek, J. Appl. Cryst.    39, 453-457, 2006.-   OLEX2, Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.;    Howard, J. A. K.; Puschmann, H., (2009). J. Appl. Cryst., 42,    339-341.-   R. W. W. Hooft et al. J. Appl. Cryst. (2008). 41. 96-103.-   H. D. Flack, Acta Cryst. 1983, A39, 867-881.

Ussing Chamber Electrophysiology Assay of CFTR Potentiation in CFBronchial Epithelial Cells

Primary cystic fibrosis human bronchial epithelial (CF hBE) cells wereexpanded and cultured according to published methods (Neuberger et al.,Ch. 4 of Cystic Fibrosis, Methods in Molecular Biology vol. 741, pp.39-54 (2011)). Well-differentiated cells (>30 days at air/liquidinterface) on Snapwell filters (Corning Costar, cat. no. 3801) weremounted in Ussing chambers (Physiologic Instruments, Inc., San Diego,Calif.). F508del/F508del cultures were assayed at 27° C. andG551D/F508del cells were assayed at 35° C. HEPES buffered physiologicalsaline (composition (in mM): 137 NaCl, 4 KCl, 1 MgCl2, 1.8 CaCl2, 10HEPES Na) was used in both apical and basolateral chambers. Chamberswere bubbled with air to promote mixing and the voltage was clamped tozero. Amiloride (30 uM), forskolin (10 uM), test compound (4 increasingconcentrations), and CFTRinh-172 (20 uM) were added sequentially with20-25 minutes between additions. Short-circuit currents were acquiredand analyzed using LabScribe2. Test compound responses were scaledrelative to responses for DMSO (0%) and the maximal response of apositive control potentiator (100%).

FRT Ion Flux Assay of F508del CFTR Potentiation

Fischer rat thyroid (FRT) cell lines stably expressing recombinantF508del V470 CFTR and halide-sensitive yellow fluorescent protein(Pedemonte et al., J. Clin. Invest. 115(9) 2564-71 (2005)) were seededat 25,000 cells/well in 50 uL/well of culture medium into black-walled,clear bottom tissue-culture-treated 384-well plates (Corning, cat. no.3712). After one day, the cells were pre-incubated at 27° C./5% CO₂ for16-24 hours. The cells were then washed with dPBS and treated withforskolin (20 uM) and test compound for 30 min by addition of 20 uL ofcompound dilution buffer (dPBS containing forskolin and test compound).Plates were loaded into FLIPR384 fluorescence imaging plate reader(Molecular Devices). After an initial fluorescence reading, iodidebuffer (25 uL) (composition (in mM): 137 NaI, 1.5 K₂PO₄, 8.1 NaH₂PO₄,2.7 KCl, 0.5 MgCl₂, 1 CaCl₂) was added and a second fluorescence readingwas made after approximately 21 seconds. Data treatment involveddivision of the second fluorescence reading by the initial fluorescencereading, then scaling of the resulting normalized endpoint fluorescencewith respect to the responses for DMSO (0%) and a positive controlpotentiator (100%).

CF hBE Ussing EC₅₀ FRT EC₅₀ Ex. No. Compound Name (nM) (nM) 14-Amino-5-[2-(difluoromethyl) pyrimidin-5-yl]-7-{1-[1-(2-fluoro 1.660.55 phenyl)-1H-pyrazol-4-yl] ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 2 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluoro 8.77 7.51 phenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine- 6-carbonitrile, enantiomer 2 34-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5- 3.36 9.17[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 44-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5- 0.56 0.61[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 54-Amino-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2- 7.73 7.69(trifluoromethyl) pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 64-Amino-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2- 1.19 1.01(trifluoromethyl) pyrimidin-5-yl)-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile, enantiomer 2 7 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}- 1.84 2.76 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile, enantiomer1 8 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}- 15.4935.18 5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 94-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- 20.3812.16 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 104-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- 70.2877.56 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 114-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- 33.47 19.80yl]ethyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 124-Amino-7-(1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol- 22.46 6.664-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 134-Amino-7-(1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol- 266.93 96.784-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 144-Amino-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2- 12.9623.61 methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 154-Amino-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2- 7.00 7.22methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6- carbonitrile,enantiomer 2 16 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-9.0 6.39yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 174-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- 49.5 45.29yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 184-Amino-7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4- 12.49 10.79yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 194-Amino-7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4- 34.70 69.62yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 204-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}- 5.48 14.155-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 214-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}- 0.45 0.875-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 224-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 6.84 4.05yl]propyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 234-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 32.50 41.79yl]propyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 244-Amino-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2- 30.00 21.52fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, single enantiomer 254-Amino-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol- 40.95 95.944-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 264-Amino-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3- 35.73 129.66triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 274-Amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2- 1.25 1.27(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 284-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- N.D. N.D.5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile 294-Amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}- 2.24 2.335-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 304-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2- 2.03 0.59fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 314-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2- N.D. N.D.(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 324-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}- N.D. N.D.5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 334-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 344-Amino-7-{1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol- N.D. N.D.4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 354-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile 364-Amino-7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile 374-Amino-7-{[1-(2-difluorophenyl)-1H-1,2,3-triazol-4- 16.28 13.53yl]methyl}-5-[2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile 384-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile 394-Amino-7-{(1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2- N.D. N.D.methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6- carbonitrile 406-Bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2- 1.30 2.18(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 416-Bromo-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}- N.D. N.D.5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 426-Bromo-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2- N.D. N.D.fluorophenyl) -1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 436-Bromo-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol- N.D. N.D.4-yl] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 446-Bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}- N.D. N.D.5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 456-Bromo-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 466-Bromo-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluoro N.D. N.D.phenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 476-Bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2- N.D. N.D.(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 486-Bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}- N.D. N.D.5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 496-Bromo-7-{1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol- N.D. N.D.4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 506-Bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5- N.D. N.D.[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin- 4-amine51 6-Bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}- N.D.N.D. 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 526-Bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 536-Bromo-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 546-Bromo-7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4- N.D. N.D.yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 556-Bromo-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluoro N.D. N.D.phenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, single enantiomer 566-Bromo-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3- N.D. N.D.triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 577-{[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoro 65.8828.80 methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 585-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 28.89231.93 4-yl] ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 595-(2-Fluoro-4-methoxyphenyl)-7-{1-[2-(2-fluorophenyl)-1H- 32.00 195.46imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 607-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-(1H- 80.00 45.26pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 617-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5- N.D. 1477.33(isoquinolin-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 627-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-(7H- N.D. 2223.78pyrrolo[2,3-b]pyridin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine 635-(6-Fluoro-2-methylquinolin-7-yl)-7-{1-[2-(2-fluorophenyl)- N.D.4536.99 1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 647-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[6- 80.28 80.00(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 657-(4-Amino-7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}- N.D.1420.13 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2H-1,4-benzoxazin-3(4H)- one 667-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-(1H- 1321.00 572.78indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 675-[2-(Dimethylamino)pyrimidin-5-yl]-7-{1-[2-(2-fluorophenyl)- 142.0054.59 1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 685-(3-Fluoro-4-methylphenyl)-7-{1-[2-(2-fluorophenyl)-1H- 26.14 111.69imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 697-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-(6- N.D. 915.49methoxy-2,3-dihydro-1H-inden-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine70 7-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[4-(2H- 30.65110.41 1,2,3-triazol-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 717-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-(1H- N.D. 129.26pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 723-(4-Amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 57.00 186.40yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- methoxybenzonitrile 737-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1- N.D. 320.24methyl-1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 745-(2,3-Dihydro-1-benzofuran-5-yl)-7-{[1-(2-fluorophenyl)-1H- 59.00328.40 1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 755-(4-Ethoxy-3-fluorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3- 38.02 99.58triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 767-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2- N.D. 2379.55methyl-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 775-[4-(Cyclopropyloxy)phenyl]-7-{[1-(2-fluorophenyl)-1H- 17.40 62.461,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 787-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1- N.D. 1378.73methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 794-(4-Amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 150.00 75.20yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- methoxybenzonitrile 807-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(7H- N.D. 3780.33pyrrolo[2,3-b]pyridin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine 817-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1H- 338.00378.76 indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 825-(4-Chloro-2-methoxyphenyl)-7-{[1-(2-fluorophenyl)-1H- 25.00 77.381,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 835-[4-(Difluoromethoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H- 39.76 71.881,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 844-(4-Amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- N.D. 1563.65yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxybenzonitrile 857-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4- 56.93 73.44methoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 867-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1- 659.00 539.38methyl-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 875-(2,4-Dimethoxyphenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- 55.00 102.18triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 887-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4- 38.17 41.28(methylsulfanyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 895-[4-(Difluoromethoxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H- 35.92 73.751,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 905-[2-Fluoro-4-(methylsulfanyl)phenyl]-7-{1-[1-(2- 34.80 45.48fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 911-[5-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- N.D. 111.23yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiophen-2- yl]ethanone 927-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(1- N.D. 2418.75methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 937-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(3- N.D. 691.00methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 947-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5- 140.00 361.46phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 957-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(1- N.D. 488.20methyl-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 961-[4-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 133.00 98.61yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]ethanone 977-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[3- 164.00230.89 (trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 985-(4-Chloro-3-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H- 27.99 40.871,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 995-(3-Chloro-5-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H- 35.90 50.001,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1007-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5- N.D. 277.25(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1016-(4-Amino-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}- N.D. 4063.277H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methyl-2,3-dihydro-1H- isoindol-1-one102 5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-7-{1-[3-(2- N.D. 321.59fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3- d]pyrimidin-4-amine103 7-{1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(1H- N.D. 5149.07pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine 1045-(2,1,3-Benzoxadiazol-5-yl)-7-{1-[3-(2-fluorophenyl)-1,2- N.D. 331.23oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1055-[4-(Dimethylamino)phenyl]-7-{1-[3-(2-fluorophenyl)-1,2- 75.00 374.14oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1067-{1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(thieno[3,2- N.D.2084.01 c] pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1077-{1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[4-(1,2,4- 122.00172.41 thiadiazol-5-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1085-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 706.361198.68 yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1095-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 68.57 36.53yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1105-Cyclobutyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 6.21 2.65yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 111 (−)5-(4-Chlorophenyl)-7-{(1R)-1-[1-(2-fluorophenyl)-1H- 135.93 533.251,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer1 112 (+) 5-(4-Chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H- 17.5068.57 1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2 113 (−)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(2- 818.00826.09 methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1 114 (+)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(2- 75.84 36.18methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2115 4-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 614.00566.01 yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile,enantiomer 1 116 4-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-26.00 36.04yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile,enantiomer 2 117 (+)5-[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H- 49.27 58.821,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer1 118 (−) 5-[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-162.50 378.281,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer2 119 (−) 5-[6-(Cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2- 187.00 676.58fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 120 (+)5-[6-(Cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2- 5.48 33.40fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1217-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(1H- 89.20 30.00pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1227-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(1H- N.D.1045.61 pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2123 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-50.54 21.63(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 1247-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- N.D.1236.99 (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1255-(6-Methoxypyridin-3-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4- 199.00395.01 yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1265-(6-Methoxypyridin-3-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4- 11.96 21.55yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 127 (−)5-(4-Methoxypyrimidin-5-yl)-7-[1-(1-phenyl-1H-1,2,3- 447.83 407.51triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1128 (+) 5-(4-Methoxypyrimidin-5-yl)-7-[1-(1-phenyl-1H-1,2,3- 42.64 19.08tnazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1297-[1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2- 10.67 8.46(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 130 7-[1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2-187.00 234.04(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 1315-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 282.00623.43 4-yl] propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1132 (+) 5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3- 11.3238.00 triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2 133 (−)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4- 721.00918.45 methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1 134 (+)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 28.90 13.41(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 135 (−)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3- 65.25202.63 methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 1 136 (+)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 3.46 15.35(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2137 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- 10.265.86 (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1387-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- 260.71265.51 (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 139 (+)5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{1-[1-(2- 3.00 5.71fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 140 (−)5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{1-[1-(2- 63.00 171.17fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 141 (−)5-[6-(Difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2- 133.00 277.11fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 142 (+)5-[6-(Difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2- 4.58 5.02fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1435-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- 25.9810.50 1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 1445-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- N.D.731.90 1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1455-[2-(Dimethylamino)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- 29.7326.03 1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 1465-[2-(Dimethylamino)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- N.D.1187.28 1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1477-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H- N.D.478.67 pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1148 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H- 25.6912.44 pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 149(+) 7-{1-[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 45.2828.89 (4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 150 (−)7-{1-[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4yl]propyl}-5-(4- 926.00297.54 methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,enantiomer 2 151 (+)7-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 35.50 34.085-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 152 (−)7-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 445.00182.50 5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 1537-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 19.7859.02 [2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1547-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 326.70630.35 [2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1557-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 9.17 38.57(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,enantiomer 1 1567-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 57.57229.77 (5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1577-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 239.00432.94 (5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1587-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 19.50112.01 (5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 159 (+)7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 35.47 18.495-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 160 (−)7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 593.00451.65 5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 161 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-10.88 8.60yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1627-{(1R)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4- 339.26 362.79yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1637-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 97.15295.97 (5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1647-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 4.58 8.18(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,enantiomer 2 1657-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 247.00727.74 (5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1667-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 9.00 24.58(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,enantiomer 2 167 5-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2,4-50.52 24.97difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1685-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2,4- 2334.47 2951.43difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1697-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 4.90 7.98(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,enantiomer 1 1707-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 48.76214.23 (5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1717-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 3.87 11.65(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,enantiomer 1 1727-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 77.56202.59 (5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 173 (−)5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 26.66 29.26yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 174 (+)7-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 31.55 19.63yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1757-{(1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2- 8.00 9.89(trifluoro methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 176 7-{(1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-106.00 203.77 (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine, enantiomer 2177 7-{1-[2-(2,4-Difluorophenyl)-2H-imidazol-4-yl]propyl}-5-[2- 18.8921.62 (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1787-{1-[2-(2,4-Difluorophenyl)-2H-imidazol-4-yl]propyl}-5-[2- N.D. 850.21(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 179 7-{1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-23.07 9.97yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1807-{1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4- N.D. 1923.65yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 181(+)-5-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5- 24.49538.07 yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 182(−)-5-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5- 445.98467.58 yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1837-{1-[3-(2-Fluorophenyl)isoxazol-5-yl]ethyl}-5-(2- 305.28 508.58methoxypyrimidin-5-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine, enantiomer 1184 7-{1-[3-(2-Fluorophenyl)isoxazol-5-yl]ethyl}-5-(2- 32.64 49.67methoxypyrimidin-5-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine, enantiomer 2185 7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 14.3634.73 [2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1867-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 296.86630.77 [2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1877-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 12.9713.18 [2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 1887-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 243.00551.27 [2-(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 1897-{1-[1-(2,4-Difluorophenyl)-5-methyl-1H-1,2,3-triazol-4- 10.18 6.72yl]propyl}-7H-pyrrolo[2,3-d] pyrimidin-4-amine, enantiomer 1 1907-{1-[1-(2,4-Difluorophenyl)-5-methyl-1H-1,2,3-triazol-4- N.D. 457.35yl]propyl}-7H-pyrrolo[2,3-d] pyrimidin-4-amine, enantiomer 2 1917-{1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(5-methoxy 103.00918.14 pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1924-(4-Amino-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}- 118.31 83.037H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile 1937-{[2-(2-Fluorophenyl)-1H-imidazol-5-yl]methyl}-5-(2- 116.56 43.77methoxy pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1947-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2- 12.21 28.59methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine 1955-(5-Fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H- 25.2963.62 1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1965-[2-(Difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H- 49.0015.59 1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1977-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1,3- 811.00254.38 oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1987-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5- 2118.00 >25000(tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1995-(2,5-Dihydrofuran-2-yl)-7-((1-(2-fluorophenyl)-1H-1,2,3- N.D. N.D.triazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2007-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4- 477.59 100.23methoxy pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 201 Noexample 201 was prepared — — 2027-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2- 798.00 922.43methoxy pyridin-3-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2037-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4- 2534.001606.59 methoxy pyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 204 5-(2-(Difluoromethyl)pyrimidin-5-yl)-7-{[1-(2-fluorophenyl)-N.D. N.D. 1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2055-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- N.D. N.D.1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2067-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2- 10.80 22.85methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2077-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(3- 238.33 225.67methoxy pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2085-(4-Chlorophenyl)-7-{1-[1-(3-methylphenyl)-1H-1,2,3- 55.00 404.18triazol-4-yl] ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2095-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 295.00343.12 4-yl]ethyl}-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2107-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2- 158.22 123.09methoxy-pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2115-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 25.92109.46 4-yl] propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2125-[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H- 12.21 68.221,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2135-[6-(Cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)- 23.11 58.631H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2145-[4-(Cyclopropoxy)phenyl]-7-{1-[1-(3-fluoropyridin-2-yl)-1H- 39.6490.62 1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2157-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(2- 183.73 79.27methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2167-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- 58.83 25.21(trifluoromethyl) pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine217 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2- N.D.N.D. (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 218 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(1H-N.D. N.D. pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2197-[1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2- N.D. N.D.(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2205-(6-methoxypyridin-3-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4- N.D. N.D.yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2215-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- N.D. N.D.1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2225-[2-(Dimethylamino)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)- N.D. N.D.1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2237-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5- 7.23 11.13fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2247-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2- 18.97 9.04(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2257-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1,3- 93.2237.31 oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2267-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H- N.D. N.D.pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2277-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin- 4-amine228 7-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D.N.D. (5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2297-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 2305-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2,4- N.D. N.D.difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2317-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 2327-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 2337-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 2347-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 2357-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. N.D.[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin- 4-amine236 5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 38.7856.00 yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2375-(6-Cyclopropoxypyridin-3-yl)-7-{1-[1-(2,4-difluorophenyl)- N.D. N.D.1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2385-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 133.00 60.57yl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2394-(4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 83.00 94.43yl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorobenzonitrile 2405-[6-(Difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)- N.D. N.D.1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2417-{1-[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- N.D. N.D.methoxy pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2425-(4-Methoxypyrimidin-5-yl)-7-(1-{1-[4- 204.53 377.79(trifluoromethyl)pyridin-2-yl]-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2437-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 95.27 56.23yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2447-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[4- 61.55 34.12methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2457-{1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. 42.44[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2467-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- N.D. 17.24[4-methoxypyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2475-Cyclobutyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 12.43 16.20yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2485-(4-Methoxypyrimidin-5-yl)-7-{1-[1-phenyl-1H-1,2,3-triazol- 55.40 25.934-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2497-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4- 27.72 12.15methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2507-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5- N.D. 2197.25(oxetan-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine 2517-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3- N.D. 5.41methoxy pyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2527-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4- 23.91 27.62methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2537-{[5-(2-Fluorophenyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(2- 1344.00719.10 methoxy pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2545-(4-Chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4- 140.00 422.22yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2555-(4-Chlorophenyl)-7-{1-[1-(cyclobutylmethyl)-1H-1,2,3- 64.70 259.42triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2565-(4-Chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 45.00341.42 4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2575-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 38.30288.88 4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2585-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5- 147.40 343.47yl]ethyl}-7H-pyrrolo[2,3-d] pyrimidin-4-amine 2595-(4-Chlorophenyl)-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5- 52.01 205.66yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2605-(4-Chlorophenyl)-7-{1-[3-(2-methoxyphenyl)-1,2-oxazol-5- 110.00 197.37yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2615-(4-Chlorophenyl)-7-{1-[3-(3-methoxyphenyl)-1,2-oxazol-5- 232.00 168.99yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2625-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-pyrazol-4- 60.22 313.23yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2635-(4-Chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5- 21.63 199.36yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2645-(4-Chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]- 35.40 176.297H-pyrrolo[2,3-d]pyrimidin-4-amine 2655-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-imidazol-4- N.D. 3876.40yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2665-(4-Chlorophenyl)-7-{1-[3-(2-methylphenyl)-1,2-oxazol-5- 252.72 138.20yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2675-(4-Chlorophenyl)-7-{1-[3-(3-fluorophenyl)-1,2-oxazol-5- 136.00 1123.17yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2687-{[1-(2-Fluorophenyl)-1H-pyrazol-3-yl]methyl}-5-(2- 578.00 470.34methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2695-(4-Chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]- 22.70478.17 7H-pyrrolo[2,3-d]pyrimidin-4-amine 2707-({1-[4-(Difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5- 47.71 451.22(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2717-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoro N.D.N.D. methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2725-(2-Methoxypyridin-3-yl)-7-[(5-phenyl-4H-1,2,4-triazol-3- 833.00 397.95yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2737-{1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4- N.D. N.D.yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2747-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2- N.D. N.D.(trifluoro methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine275 7-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2- N.D. N.D.(trifluoro methyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine276 7-{1-[2-(2,4-Difluorophenyl)-2H-imidazol-4-yl]propyl}-5-[2- N.D.N.D. (trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2777-(1-(1-(2-Fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoro N.D.N.D. methyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2787-{[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(6- 152.00218.72 methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine279 7-{[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2- N.D. N.D.(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 2805-(4-Chlorophenyl)-7-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]- 126.702667.23 7H-pyrrolo[2,3-d]pyrimidin-4-amine 2815-(4-Chlorophenyl)-7-[(1-cyclopentyl-1H-1,2,3-triazol-4- N.D. 170.33yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2825-(4-Chlorophenyl)-7-[(4-phenyl-1H-imidazol-2-yl)methyl]- 216.41 908.977H-pyrrolo[2,3-d]pyrimidin-4-amine 2835-(4-Chlorophenyl)-7-{[3-(propan-2-yl)-1,2-oxazol-5- 111.00 659.26yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2845-(4-Chlorophenyl)-7-[(5-phenyl-4H-1,2,4-triazol-3- 551.50 N.D.yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2855-(4-Chlorophenyl)-7-{[5-(2-fluorophenyl)-1H-imidazol-2- 3504.00 3694.98yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2867-{[1-(2,6-Difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-(2- 176.00 80.98methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2875-(4-Chlorophenyl)-7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3- 254.00112.12 triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 288[4-(Cyclopropyloxy)phenyl]-7-{1-[1-(3-fluoropyridin-2-yl)-1H- 39.6490.62 1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2895-Cyclopropyl-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 342.00 141.76yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2907-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2- 997.00 668.58(methoxymethyl)cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-4- amine 291 Noexample 291 was prepared — — 292[3-(4-Amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- N.D. 3205.94yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)azetidin-1- yl](cyclopropyl)methanone 293 5-{1-[(Cyclopropylmethyl)sulfonyl]azetidin-3-yl}-7-{[1-(2-N.D. 1886.61 fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2945-Cyclobutyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 189.00 167.01yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 2955-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 389.33 184.93yl]cyclopropyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2967-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(3- 50.29 123.84methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2977-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 40.14 57.50yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine298 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl}-5-245.00 179.96 (2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine299 5-(1,3-Benzoxazol-7-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3- 273.00235.15 triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 300 (−)7-{Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 453.04 154.01yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 3017-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1,3- 461.00359.89 oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 3027-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4- 297.00232.22 methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 303 (+)7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 1636.002738.32 (4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 304 (−)7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4- 134.86190.32 methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 305 (−)7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 372.00545.18 5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 306 (+) 7-{1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 26.12 22.225-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 307 (+)7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 55.39 45.805-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 1 308 (−)7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}- 430.00361.69 5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,enantiomer 2 3097-{1-[1-(6-Methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl]propyl}- 69.0069.05 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 3107-{1-[1-(6-Methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl]propyl}- N.D.1296.62 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 3117-{1-[1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 110.99249.62 [2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 1 3127-{1-[1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5- 279.001019.89 [2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 3135-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(3,4- 131.00 74.91difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 3147-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2-methoxy 357.71 230.43ethyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine 3157-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl](oxetan-3-yl) 2934.00933.26 methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 316 (+)5-Cyclopropyl-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4- 541.00 754.28yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomer 2 3175-Cyclopropyl-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}- 87.01128.66 7H-pyrrolo[2,3-d]pyrimidin-4-amine 3185-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol- 397.002992.44 4-yl]ethyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 3196-Bromo-5-(4-chlorophenyl)-7-{[1-(3-fluorophenyl)-1H-1,2,3- N.D. 193.70triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine 3204-Amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2,4- 46.19 120.14difluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 3214-Amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{1-[1-(2,4- 140.59 359.50difluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 2 3224-Amino-7-{1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4- 33.76 49.93yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomer 1 N.D. = not determined

The following data was obtained using the G551 D/F508del Ussing chamberassay performed at 35 degrees Celsius.

Example Number CF hBE EC₅₀ (nM) 27 17 134 826 161 303 162 8452

1. A pharmaceutical composition comprising a therapeutically effectiveamount of one or more of a compound of Formula I or a pharmaceuticallyacceptable salt thereof, one or more additional therapeutic agents, anda pharmaceutically acceptable carrier,

wherein W is selected from the group consisting of phenyl, which isoptionally fused with a five to six membered cycloalkyl or a five to sixmembered heterocycloalkyl comprising one, two, three, or fourheteroatoms selected independently for each occurrence from the groupconsisting of N, O and S(O)_(n); a five to ten membered heteroarylcomprising one, two, three, or four heteroatoms selected independentlyfor each occurrence from the group consisting of N, O and S(O)_(n); afour to seven membered heterocycloalkyl comprising one, two, three, orfour heteroatoms selected independently for each occurrence from thegroup consisting of N, O and S(O)_(n); and C₃-C₇ cycloalkyl; wherein thephenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one, two, three, four, or five R⁵; Y is a five memberedheteroaryl comprising one, two, three, or four heteroatoms selectedindependently for each occurrence from the group consisting of N, O andS(O)_(n), wherein the heteroaryl is optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halo, C₁-C₆alkyl, and C₁-C₆ haloalkyl; Z is selected fromthe group consisting of phenyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, a five orsix membered heteroaryl comprising one, two or three heteroatomsselected independently for each occurrence from the group consisting ofN, O and S(O)_(n), and a four to seven membered heterocycloalkylcomprising one, two, or three heteroatoms selected independently foreach occurrence from the group consisting of N, O and S(O)_(n); whereinsaid phenyl, alkyl, cycloalkyl, heteroaryl, and heterocycloalkyl areeach independently optionally substituted with one, two, three, four, orfive R⁶; R^(1a) and R^(1b) are each independently selected from thegroup consisting of —H, —OH, halo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and afour to seven membered heterocycloalkyl comprising one, two, or threeheteroatoms each independently selected from the group consisting of N,O and S(O)_(n), wherein the C₁-C₆ alkyl group is optionally substitutedwith one, two, or three substituents each independently selected fromthe group consisting of halo, —OH, C₁-C₃ alkyoxy, C₃-C₇ cycloalkyl, anda four to seven membered heterocycloalkyl comprising one, two, or threeheteroatoms each independently selected from the group consisting of N,O and S(O)_(n); and wherein each C₃-C₇ cycloalkyl and each four to sevenmembered heterocycloalkyl are optionally substituted with one, two orthree substituents independently selected for each occurrence from thegroup consisting of —OH, halo, and C₁-C₆ alkyl; or R^(1a) and R^(1b)taken together with the carbon to which they are attached form a C₃-C₇cycloalkyl or a four to seven membered heterocycloalkyl comprising one,two, or three heteroatoms each independently selected from the groupconsisting of N, O and S(O)_(n); and wherein each C₃-C₇ cycloalkyl andeach four to seven membered heterocycloalkyl are optionally substitutedwith one, two or three substituents each independently selected from thegroup consisting of —OH, halo, and C₁-C₆ alkyl. R² is selected from thegroup consisting of —H, halo, —CN, C₁-C₆ alkyl and C₁-C₆haloalkyl; R³and R⁴ are independently selected for each occurrence from the groupconsisting of —H, C₁-C₆alkyl and C₁-C₆haloalkyl; R⁵ at each occurrenceis independently selected from the group consisting of halo, —CN, C₁-C₆alkyl, C₁-C₆haloalkyl, —OR⁷, —N(R⁷)₂, —N(R⁷)C(O)R⁷, —SR⁷, oxo, C₂-C₇alkoxyalkyl, —S(O)₂C₁-C₆ alkyl, —C(O)R⁷, and a five membered heteroarylcomprising one, two, three, or four heteroatoms selected independentlyfor each occurrence from the group consisting of N, O and S(O)_(n),wherein the heteroaryl is optionally substituted with one, two, or threesubstituents independently selected for each occurrence from the groupconsisting of halo, —CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR⁷, —N(R⁷)₂ and—SR⁷; R⁶ at each occurrence is independently selected from the groupconsisting of halo, C₁-C₆ alkyl and C₁-C₆ haloalkyl, —OR⁷, —N(R⁷)₂ and—SR⁷; R⁷ is independently selected for each occurrence from the groupconsisting of —H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, andC₁-C₆alkylC₃-C₇cycloalkyl; and n at each occurrence is independently 0,1, or 2, or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, to the patient in need of treatmentthereof.
 2. The composition of claim 1, wherein R³ and R⁴ are both —H;or a pharmaceutically acceptable salt thereof.
 3. The composition ofclaim 2, wherein Y is selected from the group consisting of pyrazolyl,triazolyl, imidazolyl, and isoxazolyl, each of which is optionallysubstituted with a C₁-C₆ alkyl; or a pharmaceutically acceptable saltthereof.
 4. The composition of claim 2, wherein the moiety Y—Z isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 5. The composition ofclaim 3, wherein W is phenyl, optionally substituted with one, two, orthree R⁵; or a pharmaceutically acceptable salt thereof.
 6. Thecomposition of claim 3, wherein W is selected from the group consistingof pyrimidinyl, pyridinyl, pyrazinyl, and pyrazolyl, each optionallysubstituted with one, two, or three R⁵; or a pharmaceutically acceptablesalt thereof.
 7. The composition of claim 3, wherein W isC₃-C₇cycloalkyl, optionally substituted with one, two, or three R⁵; or apharmaceutically acceptable salt thereof.
 8. The composition of claim 6,wherein W is

optionally substituted with one, two, or three R⁵; R⁵ at each occurrenceis independently selected from the group consisting of —OCH₃, —CHF₂,—CF₃, and —N(CH₃)₂; or a pharmaceutically acceptable salt thereof. 9.The composition of claim 3, wherein Z is selected from the groupconsisting of phenyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkyl, each optionallysubstituted with one, two, or three R⁶; or a pharmaceutically acceptablesalt thereof.
 10. The composition of claim 9, wherein Z is phenyl,optionally substituted with one or two fluoro or chloro; or apharmaceutically acceptable salt thereof.
 11. The composition of claim9, wherein Z is C₁-C₆ alkyl or C₃-C₇ cycloalkyl; or a pharmaceuticallyacceptable salt thereof.
 12. The composition of claim 2, wherein R² isselected from the group consisting of: —H, —CN, and —Br; or apharmaceutically acceptable salt thereof.
 13. The composition of claim1, wherein the compound is selected from the group consisting of4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;6-bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[4-(cyclopropyloxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-cyclobutyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(6-methoxypyridin-3-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(5-fluoro-2-methoxypyridin-3-yl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[6-(difluoromethoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[2-(2,4-difluorophenyl)-1H-imidazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-5-[2-(difluoromethoxy)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;5-(2-fluoro-4-methoxyphenyl)-7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(3-fluoro-4-methylphenyl)-7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[4-(2H-1,2,3-triazol-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-ethoxy-3-fluorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chloro-2-methoxyphenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[4-(difluoromethoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-(methylsulfanyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[4-(difluoromethoxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[2-fluoro-4-(methylsulfanyl)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chloro-3-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(3-chloro-5-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;4-(4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile;5[4-(cyclopropyloxy)phenyl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-methoxypyrimidin-5-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[2-(dimethylamino)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1R)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(S)-cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(5-fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-[2-(difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{1[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;5-(4-chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-({1-[4-(difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;4-amino-5-[6-(cyclopropyloxy)pyridin-3-yl]-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;and4-amino-7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;or a pharmaceutically acceptable salt thereof.
 14. The composition ofclaim 1, wherein the compound is selected from the group consisting of7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;and4-amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;or a pharmaceutically acceptable salt thereof.
 15. The composition ofclaim 1, wherein the compound is7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineor a pharmaceutically acceptable salt thereof.
 16. The composition ofclaim 1, wherein the compound is4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.
 17. The composition ofclaim 1, wherein the compound is4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.
 18. The composition ofclaim 1, wherein the compound is4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.
 19. The composition ofclaim 1, wherein the compound is4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrileor a pharmaceutically acceptable salt thereof.
 20. The pharmaceuticalcomposition of claim 1, wherein the one or more additional therapeuticagents are independently selected from the group consisting of a CFTRpotentiator, a CFTR corrector, an epithelial sodium channel (ENaC)inhibitor, a CFTR amplifier, a CFTR stabilizer, a read-through agent, anoligonucleotide patch, an autophagy inducer, and a proteostasismodulator.
 21. The pharmaceutical composition of claim 20, wherein theCFTR potentiator at each occurrence is selected from the groupconsisting of VX-770 (Ivacaftor), GLPG-1837, GLPG-2451, QBW-251,FDL-176, FDL-129, CTP-656, and PTI-P271.
 22. The pharmaceuticalcomposition of claim 20, wherein the CFTR corrector at each occurrenceis selected from the group consisting of VX-809 (lumacaftor), VX-661(tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPG-2737, P247-A,GLPG-2222, GLPG-2665, GLPG-2851, FDL-169, and PTI-C1811.
 23. Thepharmaceutical composition of claim 20, wherein the epithelial sodiumchannel (ENaC) inhibitor at each occurrence is selected from the groupconsisting of SPX-101, QBW-276 and VX-371.
 24. The pharmaceuticalcomposition of claim 20, wherein the CFTR amplifier at each occurrenceis selected from the group consisting of PTI-428 and PTI-130.
 25. Thepharmaceutical composition of claim 20, wherein the CFTR stabilizer isN-91115 (Cavosonstat).
 26. The pharmaceutical composition of claim 20,wherein the read-through agent is ataluren.
 27. The pharmaceuticalcomposition of claim 20, wherein the oligonucleotide patch is QR-010.28. The pharmaceutical composition of claim 20, wherein the autophagyinducer at each occurrence is selected from the group consisting ofCX-4945 and the combination of cysteamine and epigallocatechin gallate(EGCG).